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Parkinson Disease: HELP
Articles by Juan C. Troncoso
Based on 23 articles published since 2010
(Why 23 articles?)
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Between 2010 and 2020, Juan Troncoso wrote the following 23 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Article Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia. 2020

Blauwendraat, Cornelis / Reed, Xylena / Krohn, Lynne / Heilbron, Karl / Bandres-Ciga, Sara / Tan, Manuela / Gibbs, J Raphael / Hernandez, Dena G / Kumaran, Ravindran / Langston, Rebekah / Bonet-Ponce, Luis / Alcalay, Roy N / Hassin-Baer, Sharon / Greenbaum, Lior / Iwaki, Hirotaka / Leonard, Hampton L / Grenn, Francis P / Ruskey, Jennifer A / Sabir, Marya / Ahmed, Sarah / Makarious, Mary B / Pihlstrøm, Lasse / Toft, Mathias / van Hilten, Jacobus J / Marinus, Johan / Schulte, Claudia / Brockmann, Kathrin / Sharma, Manu / Siitonen, Ari / Majamaa, Kari / Eerola-Rautio, Johanna / Tienari, Pentti J / Anonymous2731070 / Pantelyat, Alexander / Hillis, Argye E / Dawson, Ted M / Rosenthal, Liana S / Albert, Marilyn S / Resnick, Susan M / Ferrucci, Luigi / Morris, Christopher M / Pletnikova, Olga / Troncoso, Juan / Grosset, Donald / Lesage, Suzanne / Corvol, Jean-Christophe / Brice, Alexis / Noyce, Alastair J / Masliah, Eliezer / Wood, Nick / Hardy, John / Shulman, Lisa M / Jankovic, Joseph / Shulman, Joshua M / Heutink, Peter / Gasser, Thomas / Cannon, Paul / Scholz, Sonja W / Morris, Huw / Cookson, Mark R / Nalls, Mike A / Gan-Or, Ziv / Singleton, Andrew B. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada. · Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. · 23andMe, Inc., Mountain View, CA, USA. · Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. · Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel. · Movement Disorders Institute, Sheba Medical Center, Tel Hashomer, Israel. · The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel. · The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany. · Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland. · Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. · Department of Neurology, Helsinki University Hospital, and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland. · Neuroregeneration and Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University Medical Center, Baltimore, MD, USA. · Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA. · Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA. · Longitudinal Studies Section, National Institute on Aging, Baltimore, MD, USA. · Newcastle Brain Tissue Resource, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. · Department of Pathology (Neuropathology, Johns Hopkins University Medical Center, Baltimore, MD, USA. · Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK. · Inserm U1127, Sorbonne Universités, UPMC Univ Paris 06 UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. · Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK. · Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK. · Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA. · Department of Neurology, Baylor College of Medicine, Houston, USA. · Departments of Molecular and Human Genetics and Neuroscience, Baylor College of Medicine, Houston, USA. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, USA. · Data Tecnica International, Glen Echo, MD, USA. · Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. ·Brain · Pubmed #31755958.

ABSTRACT: Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

2 Article A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity. 2019

van der Lee, Sven J / Conway, Olivia J / Jansen, Iris / Carrasquillo, Minerva M / Kleineidam, Luca / van den Akker, Erik / Hernández, Isabel / van Eijk, Kristel R / Stringa, Najada / Chen, Jason A / Zettergren, Anna / Andlauer, Till F M / Diez-Fairen, Monica / Simon-Sanchez, Javier / Lleó, Alberto / Zetterberg, Henrik / Nygaard, Marianne / Blauwendraat, Cornelis / Savage, Jeanne E / Mengel-From, Jonas / Moreno-Grau, Sonia / Wagner, Michael / Fortea, Juan / Keogh, Michael J / Blennow, Kaj / Skoog, Ingmar / Friese, Manuel A / Pletnikova, Olga / Zulaica, Miren / Lage, Carmen / de Rojas, Itziar / Riedel-Heller, Steffi / Illán-Gala, Ignacio / Wei, Wei / Jeune, Bernard / Orellana, Adelina / Then Bergh, Florian / Wang, Xue / Hulsman, Marc / Beker, Nina / Tesi, Niccolo / Morris, Christopher M / Indakoetxea, Begoña / Collij, Lyduine E / Scherer, Martin / Morenas-Rodríguez, Estrella / Ironside, James W / van Berckel, Bart N M / Alcolea, Daniel / Wiendl, Heinz / Strickland, Samantha L / Pastor, Pau / Rodríguez Rodríguez, Eloy / Anonymous1271068 / Anonymous1281068 / Anonymous1291068 / Anonymous1301068 / Anonymous1311068 / Anonymous1321068 / Boeve, Bradley F / Petersen, Ronald C / Ferman, Tanis J / van Gerpen, Jay A / Reinders, Marcel J T / Uitti, Ryan J / Tárraga, Lluís / Maier, Wolfgang / Dols-Icardo, Oriol / Kawalia, Amit / Dalmasso, Maria Carolina / Boada, Mercè / Zettl, Uwe K / van Schoor, Natasja M / Beekman, Marian / Allen, Mariet / Masliah, Eliezer / de Munain, Adolfo López / Pantelyat, Alexander / Wszolek, Zbigniew K / Ross, Owen A / Dickson, Dennis W / Graff-Radford, Neill R / Knopman, David / Rademakers, Rosa / Lemstra, Afina W / Pijnenburg, Yolande A L / Scheltens, Philip / Gasser, Thomas / Chinnery, Patrick F / Hemmer, Bernhard / Huisman, Martijn A / Troncoso, Juan / Moreno, Fermin / Nohr, Ellen A / Sørensen, Thorkild I A / Heutink, Peter / Sánchez-Juan, Pascual / Posthuma, Danielle / Anonymous1331068 / Clarimón, Jordi / Christensen, Kaare / Ertekin-Taner, Nilüfer / Scholz, Sonja W / Ramirez, Alfredo / Ruiz, Agustín / Slagboom, Eline / van der Flier, Wiesje M / Holstege, Henne. ·Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. s.j.vanderlee@amsterdamumc.nl. · Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. s.j.vanderlee@amsterdamumc.nl. · Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, 32224, USA. · Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. · Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. · Department for Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany. · DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany. · Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine, University Hospital Cologne, Cologne, Germany. · Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. · Pattern Recognition and Bioinformatics, Delft University of Technology, Delft, The Netherlands. · Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain. · Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. · Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. · Amsterdam UMC-Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands. · Interdepartmental Program in Bioinformatics, University of California, Los Angeles, USA. · Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AgeCap) at the University of Gothenburg, Gothenburg, Sweden. · Max Planck Institute of Psychiatry, Munich, Germany. · Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · German Competence Network Multiple Sclerosis (KKNMS), Munich, Germany. · Movement Disorders and Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, Barcelona, Spain. · Fundacio per la Recerca Biomedica I Social Mutua Terrassa, Terrassa, Barcelona, Spain. · German Center for Neurodegenerative Diseases (DZNE)-Tübingen, Tübingen, Germany. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain. · Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. · Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. · Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK. · The Danish Aging Research Center, Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, 20892-3707, USA. · Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark. · Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK. · Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK. · Institut für Neuroimmunologie und Multiple Sklerose (INIMS), Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. · Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA. · Instituto Biodonostia, San Sebastian, Spain. · University Hospital "Marques de Valdecilla", Santander, Spain. · IDIVAL, Santander, Spain. · Institute of Social Medicine, Occupational Health and Public Health (ISAP), University of Leipzig, Leipzig, Germany. · Department of Neurology, University of Leipzig, Leipzig, Germany. · Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. · Newcastle Brain Tissue Resource, Edwardson Building, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK. · Cognitive Disorders Unit, Department of Neurology, Hospital Universitario San Sebastian, San Sebastian, Spain. · Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. · Department of Primary Medical Care, Center for Psychosocial Medicine, University Medical Center, Hamburg-Eppendorf, Germany. · Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH4 2XU, UK. · Department of Neurology, Klinik für Neurologie mit Institut für Translationale Neurologie, University of Münster, Münster, Germany. · Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, 55905, USA. · Department of Psychiatry and Psychology, Mayo Clinic Florida, Jacksonville, FL, 32224, USA. · Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, 32224, USA. · Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands. · Fundación Instituto Leloir-IIBBA-CONICET, Buenos Aires, Argentina. · Department of Neurology, University of Rostock, Rostock, Germany. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Department of Neurology, Hospital Universitario San Sebastian, San Sebastian, Spain. · Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, 21287, USA. · Center of Neurology, Department of Neurodegenerative diseases, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany. · MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK. · Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. · Department of Sociology, VU University, Amsterdam, The Netherlands. · Research Unit of Gynecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark. · Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Copenhagen, Denmark. · Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · MRC Integrative Epidemiology Unit, Bristol University, Bristol, UK. · Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. · Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. · Dutch Society for Research on Ageing, Leiden, The Netherlands. · Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. h.holstege@amsterdamumc.nl. · Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. h.holstege@amsterdamumc.nl. ·Acta Neuropathol · Pubmed #31131421.

ABSTRACT: The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

3 Article Assessment of APOE in atypical parkinsonism syndromes. 2019

Sabir, Marya S / Blauwendraat, Cornelis / Ahmed, Sarah / Serrano, Geidy E / Beach, Thomas G / Perkins, Matthew / Rice, Ann C / Masliah, Eliezer / Morris, Christopher M / Pihlstrom, Lasse / Pantelyat, Alexander / Resnick, Susan M / Cookson, Mark R / Hernandez, Dena G / Albert, Marilyn / Dawson, Ted M / Rosenthal, Liana S / Houlden, Henry / Pletnikova, Olga / Troncoso, Juan / Scholz, Sonja W. ·Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. · Civin Laboratory of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA. · Michigan Brain Bank, University of Michigan Medical School, Ann Arbor, MI, USA. · Virginia Commonwealth University Brain Bank, Virginia Commonwealth University, Richmond, VA, USA. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Neuroregeneration and Stem Cell Programs, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: sonja.scholz@nih.gov. ·Neurobiol Dis · Pubmed #30798004.

ABSTRACT: Atypical parkinsonism syndromes are a heterogeneous group of neurodegenerative disorders that include corticobasal degeneration (CBD), Lewy body dementia (LBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). The APOE ε4 allele is a well-established risk factor for Alzheimer's disease; however, the role of APOE in atypical parkinsonism syndromes remains controversial. To examine the associations of APOE ε4 and ε2 alleles with risk of developing these syndromes, a total of 991 pathologically-confirmed atypical parkinsonism cases were genotyped using the Illumina NeuroChip array. We also performed genotyping and logistic regression analyses to examine APOE frequency and associated risk in patients with Alzheimer's disease (n = 571) and Parkinson's disease (n = 348). APOE genotypes were compared to those from neurologically healthy controls (n = 591). We demonstrate that APOE ε4 and ε2 carriers have a significantly increased and decreased risk, respectively, of developing Alzheimer's disease (ε4: OR: 4.13, 95% CI: 3.23-5.26, p = 3.67 × 10

4 Article Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson's disease. 2018

Kam, Tae-In / Mao, Xiaobo / Park, Hyejin / Chou, Shih-Ching / Karuppagounder, Senthilkumar S / Umanah, George Essien / Yun, Seung Pil / Brahmachari, Saurav / Panicker, Nikhil / Chen, Rong / Andrabi, Shaida A / Qi, Chen / Poirier, Guy G / Pletnikova, Olga / Troncoso, Juan C / Bekris, Lynn M / Leverenz, James B / Pantelyat, Alexander / Ko, Han Seok / Rosenthal, Liana S / Dawson, Ted M / Dawson, Valina L. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. · Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Neurology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. · Centre de recherche du CHU de Québec-Pavillon CHUL, Faculté de Médecine, Université Laval, Québec G1V 4G2, Canada. · Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Lerner Research Institute, Genomic Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. · Lou Ruvo Center for Brain Health, Neurological Institute, and Department of Neurology, Cleveland Clinic, Cleveland, OH 44195, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. tdawson@jhmi.edu vdawson1@jhmi.edu. · Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. ·Science · Pubmed #30385548.

ABSTRACT: The pathologic accumulation and aggregation of α-synuclein (α-syn) underlies Parkinson's disease (PD). The molecular mechanisms by which pathologic α-syn causes neurodegeneration in PD are not known. Here, we found that pathologic α-syn activates poly(adenosine 5'-diphosphate-ribose) (PAR) polymerase-1 (PARP-1), and PAR generation accelerates the formation of pathologic α-syn, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP-1 prevented pathologic α-syn toxicity. In a feed-forward loop, PAR converted pathologic α-syn to a more toxic strain. PAR levels were increased in the cerebrospinal fluid and brains of patients with PD, suggesting that PARP activation plays a role in PD pathogenesis. Thus, strategies aimed at inhibiting PARP-1 activation could hold promise as a disease-modifying therapy to prevent the loss of dopamine neurons in PD.

5 Article Onset and Remission of Psychosis in Parkinson's Disease: Pharmacologic and Motoric Markers. 2018

Hinkle, Jared Thomas / Perepezko, Kate / Bakker, Catherine C / Broen, Martinus P G / Chin, Kathleen / Dawson, Ted M / Johnson, Vanessa / Mari, Zoltan / Marvel, Cherie L / Mills, Kelly A / Pantelyat, Alexander / Pletnikova, Olga / Rosenthal, Liana S / Shepard, Melissa D / Stevens, Daniel A / Troncoso, Juan C / Wang, Jiangxia / Pontone, Gregory M. ·Medical Scientist Training Program, Johns Hopkins School of Medicine, Baltimore, MD, United States. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States. · Morris K. Udall Parkinson's Disease Research Center, Johns Hopkins School of Medicine, Baltimore, MD, United States. · Department of Neurology, Maastricht University Medical Centre, Maastricht, the Netherlands. · Department of Neurology, Johns Hopkins School of Medicine, Baltimore MD, United States. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins School of Medicine, Baltimore MD, United States. · Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore MD, United States. · Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore MD, United States. · Cognitive Neuroscience Division, Dept. of Neurology, Johns Hopkins School of Medicine, Baltimore MD, United States. · Clinical and Neuropathology Core, Johns Hopkins School of Medicine, Baltimore MD, United States. · Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States. ·Mov Disord Clin Pract · Pubmed #29756003.

ABSTRACT: Background: Psychosis is among the most disabling complications of Parkinson's disease (PD). The chronicity of PD psychosis remains understudied and the relative importance of dopaminergic therapy versus the disease process itself in engendering psychosis remains unclear. Objectives: To examine pharmacologic and motoric correlates of PD psychosis onset and remission in a longitudinally monitored PD cohort. Methods: We analyzed data from 165 participants enrolled in a longitudinal PD study through the Morris K. Udall Parkinson's Disease Research Center of Excellence at Johns Hopkins University. Evaluations included formal psychiatric assessment and were conducted at two-year intervals. Regression with generalized estimated equations (GEE) was used to produce unadjusted and adjusted estimates for time-varying longitudinal associations between psychosis and putative risk factors. Results: Sixty-two participants (37.6%) were diagnosed with psychosis during at least one evaluation. Of forty-nine participants with psychosis followed over multiple evaluations, 13 (26.5%) demonstrated remission despite significant Hoehn & Yahr stage increase (p=0.009); two of these cases later relapsed. Multivariable regression with GEE identified dementia diagnosis, akinesia-rigidity, anticholinergic usage, and levodopa-carbidopa dose to be significantly associated with psychosis, while disease duration was not. A sub-analysis of 30 incident psychosis cases suggested that dopamine agonist dose was lowered after psychosis onset with a compensatory increase in levodopa-carbidopa dosage. Conclusions: Our findings suggest that in the context of standard therapy, PD-related psychotic disorder can remit at a frequency of approximately 27%. Additionally, akinetic-rigid motor impairment was more strongly associated with psychosis than disease duration, independent of cognitive impairment and medications.

6 Article Domain-specific cognitive impairment in non-demented Parkinson's disease psychosis. 2018

Hinkle, Jared T / Perepezko, Kate / Bakker, Catherine C / Dawson, Ted M / Johnson, Vanessa / Mari, Zoltan / Marvel, Cherie L / Mills, Kelly A / Pantelyat, Alexander / Pletnikova, Olga / Rosenthal, Liana S / Shepard, Melissa D / Stevens, Daniel A / Troncoso, Juan C / Wang, Jiangxia / Pontone, Gregory M. ·Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Morris K. Udall Parkinson's Disease Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Movement Disorders Division, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Baltimore, MD, USA. · Solomon H. Snyder Department of Neuroscience, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Cognitive Neuroscience Division, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Clinical and Neuropathology Core, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. ·Int J Geriatr Psychiatry · Pubmed #28509347.

ABSTRACT: INTRODUCTION: In Parkinson's disease (PD), psychosis is associated with cognitive impairment that may be more profound in particular cognitive domains. Our goal was to determine whether psychosis in non-demented PD participants is associated with domain-specific cognitive impairment on the Mini-Mental State Exam (MMSE). METHODS: The Morris K. Udall Parkinson's Disease Research Center of Excellence Longitudinal Study at Johns Hopkins is a prospective study that was initiated in 1998. Clinical assessments are conducted at two-year intervals at the Johns Hopkins Hospital. We analyzed data from 137 enrolled participants with idiopathic PD. Psychosis diagnoses were established by psychiatrist interview per DSM-IV criteria. An incident dementia diagnosis resulted in exclusion from analysis for that evaluation and any future evaluations in that participant. We used logistic regression with generalized estimated equations (GEE) to model the time-varying relationship between MMSE subscale scores and psychosis, adjusting for potential confounding variables identified through univariable analysis. RESULTS: Thirty-one unique psychosis cases were recorded among non-demented participants. Fifty total evaluations with psychosis present were analyzed. In multivariable regressions, psychosis was associated with lower scores on the orientation (relative odds ratio, rOR: 0.73; 95% CI: 0.58-0.93; p = 0.011), language (rOR: 0.64; 95% CI: 0.48-0.86; p = 0.003), and intersecting pentagon (rOR: 0.43; 95% CI: 0.20-0.92 p = 0.030) subscales of the MMSE. CONCLUSIONS: In PD, executive dysfunction, disorientation, and impaired language comprehension may be associated with psychosis. Our findings suggest that the corresponding MMSE subscales may be useful in identifying participants with a higher likelihood of developing psychosis. Copyright © 2017 John Wiley & Sons, Ltd.

7 Article TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau. 2016

Rousseaux, Maxime Wc / de Haro, Maria / Lasagna-Reeves, Cristian A / De Maio, Antonia / Park, Jeehye / Jafar-Nejad, Paymaan / Al-Ramahi, Ismael / Sharma, Ajay / See, Lauren / Lu, Nan / Vilanova-Velez, Luis / Klisch, Tiemo J / Westbrook, Thomas F / Troncoso, Juan C / Botas, Juan / Zoghbi, Huda Y. ·Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States. · Program in Developmental Biology, Baylor College of Medicine, Houston, Canada. · The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States. · Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States. · Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States. ·Elife · Pubmed #27779468.

ABSTRACT: Several neurodegenerative diseases are driven by the toxic gain-of-function of specific proteins within the brain. Elevated levels of alpha-synuclein (α-Syn) appear to drive neurotoxicity in Parkinson's disease (PD); neuronal accumulation of tau is a hallmark of Alzheimer's disease (AD); and their increased levels cause neurodegeneration in humans and model organisms. Despite the clinical differences between AD and PD, several lines of evidence suggest that α-Syn and tau overlap pathologically. The connections between α-Syn and tau led us to ask whether these proteins might be regulated through a shared pathway. We therefore screened for genes that affect post-translational levels of α-Syn and tau. We found that TRIM28 regulates α-Syn and tau levels and that its reduction rescues toxicity in animal models of tau- and α-Syn-mediated degeneration. TRIM28 stabilizes and promotes the nuclear accumulation and toxicity of both proteins. Intersecting screens across comorbid proteinopathies thus reveal shared mechanisms and therapeutic entry points.

8 Article Novel genetic loci underlying human intracranial volume identified through genome-wide association. 2016

Adams, Hieab H H / Hibar, Derrek P / Chouraki, Vincent / Stein, Jason L / Nyquist, Paul A / Rentería, Miguel E / Trompet, Stella / Arias-Vasquez, Alejandro / Seshadri, Sudha / Desrivières, Sylvane / Beecham, Ashley H / Jahanshad, Neda / Wittfeld, Katharina / Van der Lee, Sven J / Abramovic, Lucija / Alhusaini, Saud / Amin, Najaf / Andersson, Micael / Arfanakis, Konstantinos / Aribisala, Benjamin S / Armstrong, Nicola J / Athanasiu, Lavinia / Axelsson, Tomas / Beiser, Alexa / Bernard, Manon / Bis, Joshua C / Blanken, Laura M E / Blanton, Susan H / Bohlken, Marc M / Boks, Marco P / Bralten, Janita / Brickman, Adam M / Carmichael, Owen / Chakravarty, M Mallar / Chauhan, Ganesh / Chen, Qiang / Ching, Christopher R K / Cuellar-Partida, Gabriel / Braber, Anouk Den / Doan, Nhat Trung / Ehrlich, Stefan / Filippi, Irina / Ge, Tian / Giddaluru, Sudheer / Goldman, Aaron L / Gottesman, Rebecca F / Greven, Corina U / Grimm, Oliver / Griswold, Michael E / Guadalupe, Tulio / Hass, Johanna / Haukvik, Unn K / Hilal, Saima / Hofer, Edith / Hoehn, David / Holmes, Avram J / Hoogman, Martine / Janowitz, Deborah / Jia, Tianye / Kasperaviciute, Dalia / Kim, Sungeun / Klein, Marieke / Kraemer, Bernd / Lee, Phil H / Liao, Jiemin / Liewald, David C M / Lopez, Lorna M / Luciano, Michelle / Macare, Christine / Marquand, Andre / Matarin, Mar / Mather, Karen A / Mattheisen, Manuel / Mazoyer, Bernard / McKay, David R / McWhirter, Rebekah / Milaneschi, Yuri / Mirza-Schreiber, Nazanin / Muetzel, Ryan L / Maniega, Susana Muñoz / Nho, Kwangsik / Nugent, Allison C / Loohuis, Loes M Olde / Oosterlaan, Jaap / Papmeyer, Martina / Pappa, Irene / Pirpamer, Lukas / Pudas, Sara / Pütz, Benno / Rajan, Kumar B / Ramasamy, Adaikalavan / Richards, Jennifer S / Risacher, Shannon L / Roiz-Santiañez, Roberto / Rommelse, Nanda / Rose, Emma J / Royle, Natalie A / Rundek, Tatjana / Sämann, Philipp G / Satizabal, Claudia L / Schmaal, Lianne / Schork, Andrew J / Shen, Li / Shin, Jean / Shumskaya, Elena / Smith, Albert V / Sprooten, Emma / Strike, Lachlan T / Teumer, Alexander / Thomson, Russell / Tordesillas-Gutierrez, Diana / Toro, Roberto / Trabzuni, Daniah / Vaidya, Dhananjay / Van der Grond, Jeroen / Van der Meer, Dennis / Van Donkelaar, Marjolein M J / Van Eijk, Kristel R / Van Erp, Theo G M / Van Rooij, Daan / Walton, Esther / Westlye, Lars T / Whelan, Christopher D / Windham, Beverly G / Winkler, Anderson M / Woldehawariat, Girma / Wolf, Christiane / Wolfers, Thomas / Xu, Bing / Yanek, Lisa R / Yang, Jingyun / Zijdenbos, Alex / Zwiers, Marcel P / Agartz, Ingrid / Aggarwal, Neelum T / Almasy, Laura / Ames, David / Amouyel, Philippe / Andreassen, Ole A / Arepalli, Sampath / Assareh, Amelia A / Barral, Sandra / Bastin, Mark E / Becker, Diane M / Becker, James T / Bennett, David A / Blangero, John / van Bokhoven, Hans / Boomsma, Dorret I / Brodaty, Henry / Brouwer, Rachel M / Brunner, Han G / Buckner, Randy L / Buitelaar, Jan K / Bulayeva, Kazima B / Cahn, Wiepke / Calhoun, Vince D / Cannon, Dara M / Cavalleri, Gianpiero L / Chen, Christopher / Cheng, Ching-Yu / Cichon, Sven / Cookson, Mark R / Corvin, Aiden / Crespo-Facorro, Benedicto / Curran, Joanne E / Czisch, Michael / Dale, Anders M / Davies, Gareth E / De Geus, Eco J C / De Jager, Philip L / de Zubicaray, Greig I / Delanty, Norman / Depondt, Chantal / DeStefano, Anita L / Dillman, Allissa / Djurovic, Srdjan / Donohoe, Gary / Drevets, Wayne C / Duggirala, Ravi / Dyer, Thomas D / Erk, Susanne / Espeseth, Thomas / Evans, Denis A / Fedko, Iryna O / Fernández, Guillén / Ferrucci, Luigi / Fisher, Simon E / Fleischman, Debra A / Ford, Ian / Foroud, Tatiana M / Fox, Peter T / Francks, Clyde / Fukunaga, Masaki / Gibbs, J Raphael / Glahn, David C / Gollub, Randy L / Göring, Harald H H / Grabe, Hans J / Green, Robert C / Gruber, Oliver / Gudnason, Vilmundur / Guelfi, Sebastian / Hansell, Narelle K / Hardy, John / Hartman, Catharina A / Hashimoto, Ryota / Hegenscheid, Katrin / Heinz, Andreas / Le Hellard, Stephanie / Hernandez, Dena G / Heslenfeld, Dirk J / Ho, Beng-Choon / Hoekstra, Pieter J / Hoffmann, Wolfgang / Hofman, Albert / Holsboer, Florian / Homuth, Georg / Hosten, Norbert / Hottenga, Jouke-Jan / Hulshoff Pol, Hilleke E / Ikeda, Masashi / Ikram, M Kamran / Jack, Clifford R / Jenkinson, Mark / Johnson, Robert / Jönsson, Erik G / Jukema, J Wouter / Kahn, René S / Kanai, Ryota / Kloszewska, Iwona / Knopman, David S / Kochunov, Peter / Kwok, John B / Lawrie, Stephen M / Lemaître, Hervé / Liu, Xinmin / Longo, Dan L / Longstreth, W T / Lopez, Oscar L / Lovestone, Simon / Martinez, Oliver / Martinot, Jean-Luc / Mattay, Venkata S / McDonald, Colm / McIntosh, Andrew M / McMahon, Katie L / McMahon, Francis J / Mecocci, Patrizia / Melle, Ingrid / Meyer-Lindenberg, Andreas / Mohnke, Sebastian / Montgomery, Grant W / Morris, Derek W / Mosley, Thomas H / Mühleisen, Thomas W / Müller-Myhsok, Bertram / Nalls, Michael A / Nauck, Matthias / Nichols, Thomas E / Niessen, Wiro J / Nöthen, Markus M / Nyberg, Lars / Ohi, Kazutaka / Olvera, Rene L / Ophoff, Roel A / Pandolfo, Massimo / Paus, Tomas / Pausova, Zdenka / Penninx, Brenda W J H / Pike, G Bruce / Potkin, Steven G / Psaty, Bruce M / Reppermund, Simone / Rietschel, Marcella / Roffman, Joshua L / Romanczuk-Seiferth, Nina / Rotter, Jerome I / Ryten, Mina / Sacco, Ralph L / Sachdev, Perminder S / Saykin, Andrew J / Schmidt, Reinhold / Schofield, Peter R / Sigurdsson, Sigurdur / Simmons, Andy / Singleton, Andrew / Sisodiya, Sanjay M / Smith, Colin / Smoller, Jordan W / Soininen, Hilkka / Srikanth, Velandai / Steen, Vidar M / Stott, David J / Sussmann, Jessika E / Thalamuthu, Anbupalam / Tiemeier, Henning / Toga, Arthur W / Traynor, Bryan J / Troncoso, Juan / Turner, Jessica A / Tzourio, Christophe / Uitterlinden, Andre G / Hernández, Maria C Valdés / Van der Brug, Marcel / Van der Lugt, Aad / Van der Wee, Nic J A / Van Duijn, Cornelia M / Van Haren, Neeltje E M / Van T Ent, Dennis / Van Tol, Marie-Jose / Vardarajan, Badri N / Veltman, Dick J / Vernooij, Meike W / Völzke, Henry / Walter, Henrik / Wardlaw, Joanna M / Wassink, Thomas H / Weale, Michael E / Weinberger, Daniel R / Weiner, Michael W / Wen, Wei / Westman, Eric / White, Tonya / Wong, Tien Y / Wright, Clinton B / Zielke, H Ronald / Zonderman, Alan B / Deary, Ian J / DeCarli, Charles / Schmidt, Helena / Martin, Nicholas G / De Craen, Anton J M / Wright, Margaret J / Launer, Lenore J / Schumann, Gunter / Fornage, Myriam / Franke, Barbara / Debette, Stéphanie / Medland, Sarah E / Ikram, M Arfan / Thompson, Paul M / and others. ·Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands. · Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands. · Imaging Genetics Center, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of University of Southern California, Los Angeles, California, USA. · Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. · Lille University, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Risk factors and molecular determinants of aging-related diseases, Lille, France. · Framingham Heart Study, Framingham, Massachusetts, USA. · Department of Genetics and UNC Neuroscience Center, University of North Carolina (UNC), Chapel Hill, North Carolina, USA. · Department of Neurology, Department of Anesthesia/Critical Care Medicine, Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland, USA. · QIMR Berghofer Medical Research Institute, Brisbane, Australia. · Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. · Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. · Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands. · Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands. · Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands. · MRC-SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. · Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, Florida, USA. · John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA. · German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Greifswald, Germany. · Department of Psychiatry, University Medicine Greifswald, Greifswald, Germany. · Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht, the Netherlands. · Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada. · The Royal College of Surgeons in Ireland, Dublin 2, Ireland. · Department of Integrative Medical Biology and Umeå center for Functional Brain Imaging, Umeå University, Umeå, Sweden. · Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois, USA. · Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA. · Department of Diagnostic Radiology and Nuclear Medicine, Rush University Medical Center, Chicago, Illinois, USA. · Brain Research Imaging Centre, University of Edinburgh, Edinburgh, UK. · Department of Computer Science, Lagos State University, Lagos, Nigeria. · Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK. · Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia. · Mathematics and Statistics, Murdoch University, Perth, Australia. · NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · NORMENT - KG Jebsen Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. · Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. · Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. · Hospital for Sick Children, University of Toronto, Toronto, Canada. · Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA. · Generation R Study Group, Erasmus Medical Center, Rotterdam, the Netherlands. · Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, USA. · G.H. Sergievsky Center, Columbia University Medical Center, New York, New York, USA. · Department of Neurology, Columbia University Medical Center, New York, New York, USA. · Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA. · Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, Canada. · Department of Psychiatry and Biomedical Engineering, McGill University, Montreal, Canada. · INSERM Unit U1219, University of Bordeaux, France. · Lieber Institute for Brain Development, Baltimore, Maryland, USA. · Interdepartmental Neuroscience Graduate Program, UCLA School of Medicine, Los Angeles, California, USA. · Biological Psychology, Neuroscience Campus Amsterdam, Vrije Universiteit University and Vrije Universiteit Medical Center, Amsterdam, the Netherlands. · Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, Germany. · Department of Psychiatry, Massachusetts General Hospital, Boston, Masschusetts, USA. · Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, North Carolina, USA. · NSERM Unit 1000 ″Neuroimaging and Psychiatry″, University Paris Sud, University Paris Descartes, Paris, France. · Maison de Solenn, Adolescent Psychopathology and Medicine Department, APHP Hospital Cochin, Paris, France. · Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. · Harvard Medical School, Boston, Massachusetts, USA. · Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, Massachusetts, USA. · NORMENT - KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Norway. · Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Karakter Child and Adolescent Psychiatry University Center, Nijmegen, the Netherlands. · King's College London, Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychology, Psychiatry and Neurosciene, London, UK. · Central Institute of Mental Health, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany. · Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, Mississippi, USA. · Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands. · International Max Planck Research School for Language Sciences, Nijmegen, the Netherlands. · Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, Dresden, Germany. · Department of Research and Development, Diakonhjemmet Hospital, Oslo, Norway. · Department of Pharmacology, National University of Singapore, Singapore. · Memory Aging and Cognition Centre (MACC), National University Health System, Singapore. · Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Austria, Graz, Austria. · Institute of Medical Informatics, Statistics and Documentation, Medical University Graz, Austria, Graz, Austria. · Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Munich, Germany. · Department of Psychology, Yale University, New Haven, Connecticut, USA. · UCL Institute of Neurology, London, United Kingdom and Epilepsy Society, Bucks, UK. · Department of Medicine, Imperial College London, London, UK. · Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA. · Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA. · Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana, USA. · Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany. · Lurie Center for Autism, Massachusetts General Hospital, Harvard Medical School, Lexington, Massachusetts, USA. · Singapore Eye Research Institute, Singapore National Eye Centre, Singapore. · Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh, UK. · Donders Centre for Cognitive Neuroimaging, Radboud University, Nijmegen, The Netherlands. · Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Department of Biomedicine, Aarhus University, Aarhus, Denmark. · The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark. · Center for integrated Sequencing, iSEQ, Aarhus University, Aarhus, Denmark. · UMR5296 University of Bordeaux, CNRS, CEA, Bordeaux, France. · Department of Psychiatry, Yale University, New Haven, Connecticut, USA. · Olin Neuropsychiatric Research Center, Hartford, Connecticut, USA. · Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. · Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands. · Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland, USA. · Center for Neurobehavioral Genetics, University of California, Los Angeles, California, USA. · Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands. · Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK. · Division of Systems Neuroscience of Psychopathology, Translational Research Center, University Hospital of Psychiatry, University of Bern, Switzerland. · School of Pedagogical and Educational Sciences, Erasmus University Rotterdam, Rotterdam, the Netherlands. · Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois, USA. · Department of Medical and Molecular Genetics, King's College London, London, UK. · The Jenner Institute Laboratories, University of Oxford, Oxford, UK. · Department of Medicine and Psychiatry, University Hospital Marqués de Valdecilla, School of Medicine, University of Cantabria-IDIVAL, Santander, Spain. · CIBERSAM (Centro Investigación Biomédica en Red Salud Mental), Santander, Spain. · Psychosis Research Group, Department of Psychiatry and Trinity Translational Medicine Institute, Trinity College Dublin. · Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. · Department of Neurology, University of Miami, Miller School of Medicine, Miami, Florida, USA. · Department of Epidemiology and Public Health Sciences, University of Miami, Miller School of Medicine, Miami, Florida, USA. · Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, VIC, Australia. · Centre for Youth Mental Health, The University of Melbourne, Melbourne, VIC, Australia. · Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands. · Multimodal Imaging Laboratory, Department of Neurosciences, University of California, San Diego, USA. · Department of Cognitive Sciences, University of California, San Diego, USA. · Icelandic Heart Association, Kopavogur, Iceland. · Faculty of Medicine, University of Iceland, Reykjavik, Iceland. · Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Queensland Brain Institute, University of Queensland, Brisbane, Australia. · Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. · School of Computing Engineering and Mathematics, Western Sydney University, Parramatta, Australia. · Neuroimaging Unit,Technological Facilities. Valdecilla Biomedical Research Institute IDIVAL, Santander, Cantabria, Spain. · Institut Pasteur, Paris, France. · Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. · GeneSTAR Research Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands. · Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. · Brain Center Rudolf Magnus, Human Neurogenetics Unit, UMC Utrecht, Utrecht, the Netherlands. · Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, California, USA. · NORMENT - KG Jebsen Centre, Department of Psychology, University of Oslo, Oslo, Norway. · Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA. · FMRIB Centre, University of Oxford, Oxford, UK. · University of Wuerzburg, Department of Psychiatry, Psychosomatics and Psychotherapy, Wuerzburg, Germany. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA. · Biospective Inc, Montreal, Quebec, Canada, Montréal, Québec, Canada. · Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden. · South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine Brownsville/Edinburg/San Antonio, Texas, USA. · Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. · National Ageing Research Institute, Royal Melbourne Hospital, Melbourne, Australia. · Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne, Australia. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Dementia Collaborative Research Centre - Assessment and Better Care, UNSW, Sydney, Australia. · Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands. · Department of Psychology, Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA. · Department of Evolution and Genetics, Dagestan State University, Makhachkala, Dagestan, Russia. · The Mind Research Network and LBERI, Albuquerque, New Mexico, USA. · Department of ECE, University of New Mexico, Albuquerque, New Mexico, USA. · Centre for Neuroimaging and Cognitive Genomics (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland. · Academic Medicine Research Institute, Duke-NUS Graduate Medical School, Singapore. · Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. · Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland. · Institute of Human Genetics, University of Bonn, Bonn, Germany. · Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany. · Center for Multimodal Imaging and Genetics, University of California, San Diego, California, USA. · Department of Neurosciences, University of California, San Diego, California, USA. · Department of Radiology, University of California, San Diego, California, USA. · Department of Psychiatry, University of California, San Diego, California, USA. · Department of Cognitive Science, University of California, San Diego, California, USA. · Avera Institute for Human Genetics, Sioux Falls, South Dakota, USA. · Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. · Broad Institute, Cambridge, Massachusetts, USA. · Faculty of Health and Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, Australia. · Neurology Division, Beaumont Hospital, Dublin, 9, Ireland. · Department of Neurology, Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium. · Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. · Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition and Genomics Centre (NICOG) and NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland. · Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 8, Ireland. · Janssen Research and Development, LLC, Titusville, New Jersey, USA. · Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin, Germany. · Intramural Research Program of the National Institute on Aging, Baltimore, Maryland, USA. · Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, USA. · Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK. · Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA. · University of Texas Health Science Center, San Antonio, Texas, USA. · Division of Cerebral Integration, National Institute for Physiological Sciences, Aichi, Japan. · Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan. · Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan. · Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Department of Psychology, VU University Amsterdam, Amsterdam, the Netherlands. · Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA. · HMNC Brain Health, Munich, Germany. · Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany. · Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan. · Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA. · NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School, Baltimore, Maryland, USA. · School of Psychology, University of Sussex, Brighton, UK. · Institute of Cognitive Neuroscience, University College London, London, UK. · Department of Neuroinformatics, Araya Brain Imaging, Tokyo, Japan. · Medical University of Lodz, Lodz, Poland. · Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA. · Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA. · Neuroscience Research Australia, Sydney, Australia. · School of Medical Sciences, UNSW, Sydney, Australia. · Columbia University Medical Center, New York, New York, USA. · Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA. · Department of Neurology, University of Washington, Seattle, Washington, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Department of Psychiatry, University of Oxford, Oxford, UK. · NIHR Dementia Biomedical Research Unit, King's College London, London, UK. · Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, California, USA. (and more) ·Nat Neurosci · Pubmed #27694991.

ABSTRACT: Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ

9 Article Gait function and locus coeruleus Lewy body pathology in 51 Parkinson's disease patients. 2016

Mills, Kelly A / Mari, Zoltan / Bakker, Catherine / Johnson, Vanessa / Pontone, Gregory M / Pantelyat, Alexander / Troncoso, Juan C / Pletnikova, Olga / Dawson, Ted M / Rosenthal, Liana S. ·Movement Disorders Division, Dept. of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Meyer 6-181, Baltimore, MD, 21287, United States; Morris K. Udall Parkinson's Disease Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States. Electronic address: kmills16@jhmi.edu. · Movement Disorders Division, Dept. of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Meyer 6-181, Baltimore, MD, 21287, United States; Morris K. Udall Parkinson's Disease Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States. · Morris K. Udall Parkinson's Disease Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States. · Morris K. Udall Parkinson's Disease Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Clinical and Neuropathology Core, Johns Hopkins University School of Medicine, Baltimore, MD, United States. · Movement Disorders Division, Dept. of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Meyer 6-181, Baltimore, MD, 21287, United States; Morris K. Udall Parkinson's Disease Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, United States; Solomon H. Snyder Department of Neuroscience, United States; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, 21205, United States. ·Parkinsonism Relat Disord · Pubmed #27693194.

ABSTRACT: INTRODUCTION: Gait impairment in Parkinson's Disease (PD) is often severely disabling, yet frequently remains refractory to treatment. The locus coeruleus (LC) has diffuse noradrenergic projections that are thought to play a role in gait function. Enhancement of norepinephrine transmission may improve gait in some PD patients. We hypothesized that the severity of PD pathology, and more specifically, Lewy bodies and neuronal loss in the LC, would correlate with the severity of gait dysfunction in PD. METHODS: Autopsy data from 51 patients, collected through the Morris K. Udall Parkinson's Disease Research Center, were correlated with clinical gait-related measures, including individual Unified Parkinson's Disease Rating Scale (UPDRS) Part II and III questions, total UPDRS Part III scores, and timed up-and-go speed (TUG). RESULTS: Neither the presence nor degree of Lewy body pathology in the LC on autopsy was associated with a higher UPDRS part III gait score. LC tau deposition and frontal Lewy body deposition were not correlated with any of the assessed gait measures. The degree of Lewy body pathology, independent of Braak stage, was positively associated with the severity of motor symptoms overall (UPDRS Part III total score). CONCLUSION: Neither the degree of Lewy body nor tau pathology in the LC is associated with severity of gait disorders in PD. This finding may have implications for targeted noradrenergic therapies in patients with refractory gait disorders.

10 Article Adult Conditional Knockout of PGC-1α Leads to Loss of Dopamine Neurons. 2016

Jiang, Haisong / Kang, Sung-Ung / Zhang, Shuran / Karuppagounder, Senthilkumar / Xu, Jinchong / Lee, Yong-Kyu / Kang, Bong-Gu / Lee, Yunjong / Zhang, Jianmin / Pletnikova, Olga / Troncoso, Juan C / Pirooznia, Shelia / Andrabi, Shaida A / Dawson, Valina L / Dawson, Ted M. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130-2685. · Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130-2685. · Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130-2685; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130-2685; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. ·eNeuro · Pubmed #27622213.

ABSTRACT: Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder. Recent studies have implicated a role for peroxisome proliferator-activated receptor γ coactivator protein-1α (PGC-1α) in PD and in animal or cellular models of PD. The role of PGC-1α in the function and survival of substantia nigra pars compacta (SNpc) dopamine neurons is not clear. Here we find that there are four different PGC-1α isoforms expressed in SH-SY5Y cells, and these four isoforms are expressed across subregions of mouse brain. Adult conditional PGC-1α knock-out mice show a significant loss of dopaminergic neurons that is accompanied by a reduction of dopamine in the striatum. In human PD postmortem tissue from the SNpc, there is a reduction of PGC-1α isoforms and mitochondria markers. Our findings suggest that all four isoforms of PGC-1α are required for the proper expression of mitochondrial proteins in SNpc DA neurons and that PGC-1α is essential for SNpc DA neuronal survival, possibly through the maintenance of mitochondrial function.

11 Article Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration. 2016

Brahmachari, Saurav / Ge, Preston / Lee, Su Hyun / Kim, Donghoon / Karuppagounder, Senthilkumar S / Kumar, Manoj / Mao, Xiaobo / Shin, Joo Ho / Lee, Yunjong / Pletnikova, Olga / Troncoso, Juan C / Dawson, Valina L / Dawson, Ted M / Ko, Han Seok. · ·J Clin Invest · Pubmed #27348587.

ABSTRACT: Aggregation of α-synuclein contributes to the formation of Lewy bodies and neurites, the pathologic hallmarks of Parkinson disease (PD) and α-synucleinopathies. Although a number of human mutations have been identified in familial PD, the mechanisms that promote α-synuclein accumulation and toxicity are poorly understood. Here, we report that hyperactivity of the nonreceptor tyrosine kinase c-Abl critically regulates α-synuclein-induced neuropathology. In mice expressing a human α-synucleinopathy-associated mutation (hA53Tα-syn mice), deletion of the gene encoding c-Abl reduced α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Conversely, overexpression of constitutively active c-Abl in hA53Tα-syn mice accelerated α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Moreover, c-Abl activation led to an age-dependent increase in phosphotyrosine 39 α-synuclein. In human postmortem samples, there was an accumulation of phosphotyrosine 39 α-synuclein in brain tissues and Lewy bodies of PD patients compared with age-matched controls. Furthermore, in vitro studies show that c-Abl phosphorylation of α-synuclein at tyrosine 39 enhances α-synuclein aggregation. Taken together, this work establishes a critical role for c-Abl in α-synuclein-induced neurodegeneration and demonstrates that selective inhibition of c-Abl may be neuroprotective. This study further indicates that phosphotyrosine 39 α-synuclein is a potential disease indicator for PD and related α-synucleinopathies.

12 Article Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1. 2016

Nucifora, Frederick C / Nucifora, Leslie G / Ng, Chee-Hoe / Arbez, Nicolas / Guo, Yajuan / Roby, Elaine / Shani, Vered / Engelender, Simone / Wei, Dong / Wang, Xiao-Fang / Li, Tianxia / Moore, Darren J / Pletnikova, Olga / Troncoso, Juan C / Sawa, Akira / Dawson, Ted M / Smith, Wanli / Lim, Kah-Leong / Ross, Christopher A. ·Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. · Danone Nutricia Research, 30 Biopolis Street, Matrix Building, #05-01B, Singapore 138671, Singapore. · Department of Molecular Pharmacology, Rappaport Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel. · Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, USA. · Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA. · Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA. · Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA. · Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685, USA. · Neuroscience and Behavioral Disorders Program, Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore. · Department of Physiology, National University of Singapore, Singapore 117543, Singapore. ·Nat Commun · Pubmed #27273569.

ABSTRACT: A common genetic form of Parkinson's disease (PD) is caused by mutations in LRRK2. We identify WSB1 as a LRRK2 interacting protein. WSB1 ubiquitinates LRRK2 through K27 and K29 linkage chains, leading to LRRK2 aggregation and neuronal protection in primary neurons and a Drosophila model of G2019S LRRK2. Knocking down endogenous WSB1 exacerbates mutant LRRK2 neuronal toxicity in neurons and the Drosophila model, indicating a role for endogenous WSB1 in modulating LRRK2 cell toxicity. WSB1 is in Lewy bodies in human PD post-mortem tissue. These data demonstrate a role for WSB1 in mutant LRRK2 pathogenesis, and suggest involvement in Lewy body pathology in sporadic PD. Our data indicate a role in PD for ubiquitin K27 and K29 linkages, and suggest that ubiquitination may be a signal for aggregation and neuronal protection in PD, which may be relevant for other neurodegenerative disorders. Finally, our study identifies a novel therapeutic target for PD.

13 Article PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease. 2015

Beecham, Gary W / Dickson, Dennis W / Scott, William K / Martin, Eden R / Schellenberg, Gerard / Nuytemans, Karen / Larson, Eric B / Buxbaum, Joseph D / Trojanowski, John Q / Van Deerlin, Vivianna M / Hurtig, Howard I / Mash, Deborah C / Beach, Thomas G / Troncoso, Juan C / Pletnikova, Olga / Frosch, Matthew P / Ghetti, Bernardino / Foroud, Tatiana M / Honig, Lawrence S / Marder, Karen / Vonsattel, Jean Paul / Goldman, Samuel M / Vinters, Harry V / Ross, Owen A / Wszolek, Zbigniew K / Wang, Liyong / Dykxhoorn, Derek M / Pericak-Vance, Margaret A / Montine, Thomas J / Leverenz, James B / Dawson, Ted M / Vance, Jeffery M. ·From the John P. Hussman Institute for Human Genomics (G.W.B., W.K.S., E.R.M., K.N., L.W., D.M.D., M.A.P.-V., J.M.V.) and University of Miami Brain Endowment Bank (D.C.M.), Miller School of Medicine, University of Miami, FL · Departments of Neuroscience (D.W.D., O.A.R.) and Neurology (Z.K.W.), Mayo Clinic Florida, Jacksonville · Department of Pathology & Laboratory Medicine (G.S., J.Q.T., V.M.V.D., H.I.H.), Perelman School of Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia · Group Health Research Institute (E.B.L.), Seattle, WA · Departments of Psychiatry, and Genetics and Genomic Sciences (J.D.B.), Mount Sinai School of Medicine, New York, NY · Arizona Alzheimer's Consortium (T.G.B.), Phoenix · Sun Health Research Institute (T.G.B.), Sun City, AZ · Division of Neuropathology, Department of Pathology (J.C.T., O.P.), and Department of Neurology and the Solomon H. Snyder Department of Neuroscience (T.M.D.), Johns Hopkins University School of Medicine, Baltimore, MD · Kubik Laboratory for Neuropathology (M.P.F.), Massachusetts General Hospital and Harvard Medical School, Charlestown, MA · Department of Pathology and Laboratory Medicine, Indiana Alzheimer Disease Center (B.G.), and Department of Medical and Molecular Genetics (T.M.F.), Indiana University School of Medicine, Indianapolis · Departments of Neurology (L.S.H., K.M.) and Psychiatry (K.M.), Gertrude H. Sergievsky Center, and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York · Department of Pathology and Cell Biology (J.P.V.), Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY · The Parkinson's Institute (S.M.G.), Sunnyvale, CA · Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology (H.V.V.), David Geffen School of Medicine at University of California Los Angeles · Department of Pathology (T.J.M.), University of Washington School of Medicine, Seattle · VA Puget Sound Health Care System ( ·Neurology · Pubmed #25663231.

ABSTRACT: OBJECTIVE: To minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls. METHODS: Four hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis. RESULTS: A small region on chromosome 1 was strongly associated with PD (rs10788972; p = 6.2 × 10(-8)). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2, TMEM59, miR-4781, and LDLRAD1. CONCLUSIONS: We confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD.

14 Article Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation. 2014

Liu, Guoxiang / Yu, Jia / Ding, Jinhui / Xie, Chengsong / Sun, Lixin / Rudenko, Iakov / Zheng, Wang / Sastry, Namratha / Luo, Jing / Rudow, Gay / Troncoso, Juan C / Cai, Huaibin. · ·J Clin Invest · Pubmed #24865427.

ABSTRACT: Subpopulations of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) display a differential vulnerability to loss in Parkinson's disease (PD); however, it is not clear why these subsets are preferentially selected in PD-associated neurodegeneration. In rodent SNpc, DA neurons can be divided into two subpopulations based on the expression of aldehyde dehydrogenase 1 (ALDH1A1). Here, we have shown that, in α-synuclein transgenic mice, a murine model of PD-related disease, DA neurodegeneration occurs mainly in a dorsomedial ALDH1A1-negative subpopulation that is also prone to cytotoxic aggregation of α-synuclein. Notably, the topographic ALDH1A1 pattern observed in α-synuclein transgenic mice was conserved in human SNpc. Postmortem evaluation of brains of patients with PD revealed a severe reduction of ALDH1A1 expression and neurodegeneration in the ventral ALDH1A1-positive DA subpopulations. ALDH1A1 expression was also suppressed in α-synuclein transgenic mice. Deletion of Aldh1a1 exacerbated α-synuclein-mediated DA neurodegeneration and α-synuclein aggregation, whereas Aldh1a1-null and control DA neurons were comparably susceptible to 1-methyl-4-phenylpyridinium-, glutamate-, or camptothecin-induced cell death. ALDH1A1 overexpression appeared to preferentially protect against α-synuclein-mediated DA neurodegeneration but did not rescue α-synuclein-induced loss of cortical neurons. Together, our findings suggest that ALDH1A1 protects subpopulations of SNpc DA neurons by preventing the accumulation of dopamine aldehyde intermediates and formation of cytotoxic α-synuclein oligomers.

15 Article Parkinson's disease-linked mutations in VPS35 induce dopaminergic neurodegeneration. 2014

Tsika, Elpida / Glauser, Liliane / Moser, Roger / Fiser, Aris / Daniel, Guillaume / Sheerin, Una-Marie / Lees, Andrew / Troncoso, Juan C / Lewis, Patrick A / Bandopadhyay, Rina / Schneider, Bernard L / Moore, Darren J. ·Laboratory of Molecular Neurodegenerative Research. · Department of Molecular Neuroscience. · Queen Square Brain Bank for Neurological Disorders, University College London Institute of Neurology, London WC1N 3BG, UK. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Molecular Neuroscience School of Pharmacy, University of Reading, Reading RG6 6AP, UK. · Reta Lila Weston Institute of Neurological Studies, University College London Institute of Neurology, London WC1N 1PJ, UK. · Neurodegenerative Disease Laboratory, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. · Laboratory of Molecular Neurodegenerative Research Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USA darren.moore@vai.org. ·Hum Mol Genet · Pubmed #24740878.

ABSTRACT: Mutations in the vacuolar protein sorting 35 homolog (VPS35) gene at the PARK17 locus, encoding a key component of the retromer complex, were recently identified as a new cause of late-onset, autosomal dominant Parkinson's disease (PD). Here we explore the pathogenic consequences of PD-associated mutations in VPS35 using a number of model systems. VPS35 exhibits a broad neuronal distribution throughout the rodent brain, including within the nigrostriatal dopaminergic pathway. In the human brain, VPS35 protein levels and distribution are similar in tissues from control and PD subjects, and VPS35 is not associated with Lewy body pathology. The common D620N missense mutation in VPS35 does not compromise its protein stability or localization to endosomal and lysosomal vesicles, or the vesicular sorting of the retromer cargo, sortilin, SorLA and cation-independent mannose 6-phosphate receptor, in rodent primary neurons or patient-derived human fibroblasts. In yeast we show that PD-linked VPS35 mutations are functional and can normally complement VPS35 null phenotypes suggesting that they do not result in a loss-of-function. In rat primary cortical cultures the overexpression of human VPS35 induces neuronal cell death and increases neuronal vulnerability to PD-relevant cellular stress. In a novel viral-mediated gene transfer rat model, the expression of D620N VPS35 induces the marked degeneration of substantia nigra dopaminergic neurons and axonal pathology, a cardinal pathological hallmark of PD. Collectively, these studies establish that dominant VPS35 mutations lead to neurodegeneration in PD consistent with a gain-of-function mechanism, and support a key role for VPS35 in the development of PD.

16 Article Beta-amyloid, phospho-tau and alpha-synuclein deposits similar to those in the brain are not identified in the eyes of Alzheimer's and Parkinson's disease patients. 2014

Ho, Cheng-Ying / Troncoso, Juan C / Knox, David / Stark, Walter / Eberhart, Charles G. ·Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD. ·Brain Pathol · Pubmed #23714377.

ABSTRACT: Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders, and are characterized by deposition of specific proteins in the brain. If similar abnormal protein deposits are present in the eye, it would facilitate noninvasive diagnosis and monitoring of disease progression. We therefore evaluated expression of proteins associated with AD and PD pathology in postmortem eyes and brains in a case-control study. Eyes from 11 cases of AD, 6 cases of PD or PD with dementia, and 6 age-matched controls were retrieved from the autopsy archives of The Johns Hopkins Hospital. Immunostains for β-amyloid, phospho-tau and α-synuclein and Congo red stains were performed in the same laboratory in both brains and eyes. No amyloid deposits or abnormal tau accumulations were detected in the lens, retina or other structures in the eyes of AD patients. Eyes also lacked definite Lewy bodies or Lewy neurites in either PD or AD cases. Patchy cytoplasmic α-synuclein positivity was seen in the retina of AD, PD and control cases, but did not correlate with the presence or extent of Lewy body pathology in the brain. Abnormal protein aggregations characteristic of AD and PD are thus not commonly present in the retinas or lens of affected patients when assayed using the same protocols as in the brain. This suggests that β-amyloid, phospho-tau and α-synuclein either do not deposit in the eye in a manner analogous to brain, or are present at lower levels or in different forms.

17 Article MicroRNA-205 regulates the expression of Parkinson's disease-related leucine-rich repeat kinase 2 protein. 2013

Cho, Hyun Jin / Liu, Guoxiang / Jin, Seok Min / Parisiadou, Loukia / Xie, Chengsong / Yu, Jia / Sun, Lixin / Ma, Bo / Ding, Jinhui / Vancraenenbroeck, Renée / Lobbestael, Evy / Baekelandt, Veerle / Taymans, Jean-Marc / He, Ping / Troncoso, Juan C / Shen, Yong / Cai, Huaibin. ·Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. ·Hum Mol Genet · Pubmed #23125283.

ABSTRACT: Recent genome-wide association studies indicate that a simple alteration of Leucine-rich repeat kinase 2 (LRRK2) gene expression may contribute to the etiology of sporadic Parkinson's disease (PD). However, the expression and regulation of LRRK2 protein in the sporadic PD brains remain to be determined. Here, we found that the expression of LRRK2 protein was enhanced in the sporadic PD patients using the frontal cortex tissue from a set of 16 PD patients and 7 control samples. In contrast, no significant difference was detected in the level of LRRK2 mRNA expression between the control and PD cases, suggesting a potential post-transcriptional modification of the LRRK2 protein expression in the sporadic PD brains. Indeed, it was identified that microRNA-205 (miR-205) suppressed the expression of LRRK2 protein through a conserved-binding site at the 3'-untranslated region (UTR) of LRRK2 gene. Interestingly, miR-205 expression was significantly downregulated in the brains of patients with sporadic PD, showing the enhanced LRRK2 protein levels. Also, in vitro studies in the cell lines and primary neuron cultures further established the role of miR-205 in modulating the expression of LRRK2 protein. In addition, introduction of miR-205 prevented the neurite outgrowth defects in the neurons expressing a PD-related LRRK2 R1441G mutant. Together, these findings suggest that downregulation of miR-205 may contribute to the potential pathogenic elevation of LRRK2 protein in the brains of patients with sporadic PD, while overexpression of miR-205 may provide an applicable therapeutic strategy to suppress the abnormal upregulation of LRRK2 protein in PD.

18 Article Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo. 2012

Colla, Emanuela / Coune, Philippe / Liu, Ying / Pletnikova, Olga / Troncoso, Juan C / Iwatsubo, Takeshi / Schneider, Bernard L / Lee, Michael K. ·Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ·J Neurosci · Pubmed #22399753.

ABSTRACT: Accumulation of misfolded α-synuclein (αS) is mechanistically linked to neurodegeneration in Parkinson's disease (PD) and other α-synucleinopathies. However, how αS causes neurodegeneration is unresolved. Because cellular accumulation of misfolded proteins can lead to endoplasmic reticulum stress/unfolded protein response (ERS/UPR), chronic ERS could contribute to neurodegeneration in α-synucleinopathy. Using the A53T mutant human αS transgenic (A53TαS Tg) mouse model of α-synucleinopathy, we show that disease onset in the αS Tg model is coincident with induction of ER chaperones in neurons exhibiting αS pathology. However, the neuronal ER chaperone induction was not accompanied by the activation of phospho-eIF2α, indicating that α-synucleinopathy is associated with abnormal UPR that could promote cell death. Induction of ERS/UPR was associated with increased levels of ER/microsomal (ER/M) associated αS monomers and aggregates. Significantly, human PD cases also exhibit higher relative levels of ER/M αS than the control cases. Moreover, αS interacts with ER chaperones and overexpression of αS sensitizes neuronal cells to ERS-induced toxicity, suggesting that αS may have direct impact on ER function. This view is supported by the presence of ERS-activated caspase-12 and the accumulation of ER-associated polyubiquitin. More important, treatment with Salubrinal, an anti-ERS compound, significantly attenuates disease manifestations in both the A53TαS Tg mouse model and the adeno-associated virus-transduced rat model of A53TαS-dependent dopaminergic neurodegeneration. Our data indicate that the accumulation αS within ER leads to chronic ER stress conditions that contribute to neurodegeneration in α-synucleinopathies. Attenuating chronic ERS could be an effective therapy for PD and other α-synucleinopathies.

19 Article Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo. 2012

Colla, Emanuela / Jensen, Poul H / Pletnikova, Olga / Troncoso, Juan C / Glabe, Charles / Lee, Michael K. ·Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ·J Neurosci · Pubmed #22399752.

ABSTRACT: In Parkinson's disease (PD) and other α-synucleinopathies, prefibrillar α-synuclein (αS) oligomer is implicated in the pathogenesis. However, toxic αS oligomers observed using in vitro systems are not generally seen to be associated with α-synucleinopathy in vivo. Thus, the pathologic significance of αS oligomers to αS neurotoxicity is unknown. Herein, we show that, αS that accumulate within endoplasmic reticulum (ER)/microsome forms toxic oligomers in mouse and human brain with the α-synucleinopathy. In the mouse model of α-synucleinopathy, αS oligomers initially form before the onset of disease and continue to accumulate with the disease progression. Significantly, treatment of αS transgenic mice with Salubrinal, an anti-ER stress compound that delays the onset of disease, reduces ER accumulation of αS oligomers. These results indicate that αS oligomers with toxic conformation accumulate in ER, and αS oligomer-dependent ER stress is pathologically relevant for PD.

20 Article PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity. 2012

Ramonet, David / Podhajska, Agata / Stafa, Klodjan / Sonnay, Sarah / Trancikova, Alzbeta / Tsika, Elpida / Pletnikova, Olga / Troncoso, Juan C / Glauser, Liliane / Moore, Darren J. ·Laboratory of Molecular Neurodegenerative Research, School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. ·Hum Mol Genet · Pubmed #22186024.

ABSTRACT: Mutations in the ATP13A2 gene (PARK9, OMIM 610513) cause autosomal recessive, juvenile-onset Kufor-Rakeb syndrome and early-onset parkinsonism. ATP13A2 is an uncharacterized protein belonging to the P(5)-type ATPase subfamily that is predicted to regulate the membrane transport of cations. The physiological function of ATP13A2 in the mammalian brain is poorly understood. Here, we demonstrate that ATP13A2 is localized to intracellular acidic vesicular compartments in cultured neurons. In the human brain, ATP13A2 is localized to pyramidal neurons within the cerebral cortex and dopaminergic neurons of the substantia nigra. ATP13A2 protein levels are increased in nigral dopaminergic and cortical pyramidal neurons of Parkinson's disease brains compared with normal control brains. ATP13A2 levels are increased in cortical neurons bearing Lewy bodies (LBs) compared with neurons without LBs. Using short hairpin RNA-mediated silencing or overexpression to explore the function of ATP13A2, we find that modulating the expression of ATP13A2 reduces the neurite outgrowth of cultured midbrain dopaminergic neurons. We also find that silencing of ATP13A2 expression in cortical neurons alters the kinetics of intracellular pH in response to cadmium exposure. Furthermore, modulation of ATP13A2 expression leads to reduced intracellular calcium levels in cortical neurons. Finally, we demonstrate that silencing of ATP13A2 expression induces mitochondrial fragmentation in neurons. Oppositely, overexpression of ATP13A2 delays cadmium-induced mitochondrial fragmentation in neurons consistent with a neuroprotective effect. Collectively, this study reveals a number of intriguing neuronal phenotypes due to the loss- or gain-of-function of ATP13A2 that support a role for this protein in regulating intracellular cation homeostasis and neuronal integrity.

21 Article Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function. 2010

Ko, Han Seok / Lee, Yunjong / Shin, Joo-Ho / Karuppagounder, Senthilkumar S / Gadad, Bharathi Shrikanth / Koleske, Anthony J / Pletnikova, Olga / Troncoso, Juan C / Dawson, Valina L / Dawson, Ted M. ·Neuroregeneration Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. ·Proc Natl Acad Sci U S A · Pubmed #20823226.

ABSTRACT: Mutations in PARK2/Parkin, which encodes a ubiquitin E3 ligase, cause autosomal recessive Parkinson disease (PD). Here we show that the nonreceptor tyrosine kinase c-Abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin E3 ligase activity and protective function. c-Abl is activated by dopaminergic stress and by dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP(+)) in vitro and in vivo by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), leading to parkin inactivation, accumulation of the parkin substrates aminoacyl-tRNA synthetase-interacting multifunctional protein type 2 (AIMP2) (p38/JTV-1) and fuse-binding protein 1 (FBP1), and cell death. STI-571, a c-Abl-family kinase inhibitor, prevents the phosphorylation of parkin, maintaining parkin in a catalytically active and protective state. STI-571's protective effects require parkin, as shRNA knockdown of parkin prevents STI-571 protection. Conditional knockout of c-Abl in the nervous system also prevents the phosphorylation of parkin, the accumulation of its substrates, and subsequent neurotoxicity in response to MPTP intoxication. In human postmortem PD brain, c-Abl is active, parkin is tyrosine-phosphorylated, and AIMP2 and FBP1 accumulate in the substantia nigra and striatum. Thus, tyrosine phosphorylation of parkin by c-Abl is a major posttranslational modification that inhibits parkin function, possibly contributing to pathogenesis of sporadic PD. Moreover, inhibition of c-Abl may be a neuroprotective approach in the treatment of PD.

22 Article Synphilin-1 attenuates neuronal degeneration in the A53T alpha-synuclein transgenic mouse model. 2010

Smith, Wanli W / Liu, Zhaohui / Liang, Yideng / Masuda, Naoki / Swing, Debbie A / Jenkins, Nancy A / Copeland, Neal G / Troncoso, Juan C / Pletnikov, Mikhail / Dawson, Ted M / Martin, Lee J / Moran, Timothy H / Lee, Michael K / Borchelt, David R / Ross, Christopher A. ·Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. ·Hum Mol Genet · Pubmed #20185556.

ABSTRACT: Genetic alterations in alpha-synuclein cause autosomal dominant familial Parkinsonism and may contribute to sporadic Parkinson's disease (PD). Synphilin-1 is an alpha-synuclein-interacting protein, with implications in PD pathogenesis related to protein aggregation. Currently, the in vivo role of synphilin-1 in alpha-synuclein-linked pathogenesis is not fully understood. Using the mouse prion protein promoter, we generated synphilin-1 transgenic mice, which did not display PD-like phenotypes. However, synphilin-1/A53T alpha-synuclein double-transgenic mice survived longer than A53T alpha-synuclein single-transgenic mice. There were attenuated A53T alpha-synuclein-induced motor abnormalities and decreased astroglial reaction and neuronal degeneration in brains in double-transgenic mice. Overexpression of synphilin-1 decreased caspase-3 activation, increased beclin-1 and LC3 II expression and promoted formation of aggresome-like structures, suggesting that synphilin-1 alters multiple cellular pathways to protect against neuronal degeneration. These studies demonstrate that synphilin-1 can diminish the severity of alpha-synucleinopathy and play a neuroprotective role against A53T alpha-synuclein toxicity in vivo.

23 Minor ADORA1 mutations are not a common cause of Parkinson's disease and dementia with Lewy bodies. 2017

Blauwendraat, Cornelis / Nalls, Mike A / Federoff, Monica / Pletnikova, Olga / Ding, Jinhui / Letson, Christopher / Geiger, Joshua T / Gibbs, J Raphael / Hernandez, Dena G / Troncoso, Juan C / Simón-Sánchez, Javier / Scholz, Sonja W / Anonymous6391022. ·Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Contractor/consultant with Kelly Services, Rockville, Maryland, USA. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland, USA. ·Mov Disord · Pubmed #27987235.

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