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Parkinson Disease: HELP
Articles by Joshua M. Shulman
Based on 16 articles published since 2010
(Why 16 articles?)
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Between 2010 and 2020, Joshua M. Shulman wrote the following 16 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Editorial Structural variation and the expanding genomic architecture of Parkinson disease. 2013

Shulman, Joshua M. ·Departments of Neurology and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas2Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston. ·JAMA Neurol · Pubmed #24018918.

ABSTRACT: -- No abstract --

2 Editorial Molecular mechanisms of cortical degeneration in Parkinson disease. 2012

Shulman, Joshua M / Schneider, Julie A. ·Department of Neurology, Baylor College of Medicine, Houston, TX, USA. ·Neurology · Pubmed #23019261.

ABSTRACT: -- No abstract --

3 Review Progress toward an integrated understanding of Parkinson's disease. 2017

Rousseaux, Maxime W C / Shulman, Joshua M / Jankovic, Joseph. ·Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund St, Houston, TX, 77030, USA. · Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. · Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 7200 Cambridge, Houston, TX, 77030-4202, USA. · Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. ·F1000Res · Pubmed #28751973.

ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting over 10 million individuals worldwide. While numerous effective symptomatic treatments are currently available, no curative or disease-modifying therapies exist. An integrated, comprehensive understanding of PD pathogenic mechanisms will likely address this unmet clinical need. Here, we highlight recent progress in PD research with an emphasis on promising translational findings, including (i) advances in our understanding of disease susceptibility, (ii) improved knowledge of cellular dysfunction, and (iii) insights into mechanisms of spread and propagation of PD pathology. We emphasize connections between these previously disparate strands of PD research and the development of an emerging systems-level understanding that will enable the next generation of PD therapeutics.

4 Review A mitocentric view of Parkinson's disease. 2014

Haelterman, Nele A / Yoon, Wan Hee / Sandoval, Hector / Jaiswal, Manish / Shulman, Joshua M / Bellen, Hugo J. ·Program in Developmental Biology. ·Annu Rev Neurosci · Pubmed #24821430.

ABSTRACT: Parkinson's disease (PD) is a common neurodegenerative disease, yet the underlying causative molecular mechanisms are ill defined. Numerous observations based on drug studies and mutations in genes that cause PD point to a complex set of rather subtle mitochondrial defects that may be causative. Indeed, intensive investigation of these genes in model organisms has revealed roles in the electron transport chain, mitochondrial protein homeostasis, mitophagy, and the fusion and fission of mitochondria. Here, we attempt to synthesize results from experimental studies in diverse systems to define the precise function of these PD genes, as well as their interplay with other genes that affect mitochondrial function. We propose that subtle mitochondrial defects in combination with other insults trigger the onset and progression of disease, in both familial and idiopathic PD.

5 Review Parkinson's disease: genetics and pathogenesis. 2011

Shulman, Joshua M / De Jager, Philip L / Feany, Mel B. ·Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA. jshulman2@partners.org ·Annu Rev Pathol · Pubmed #21034221.

ABSTRACT: Recent investigation into the mechanisms of Parkinson's disease (PD) has generated remarkable insight while simultaneously challenging traditional conceptual frameworks. Although the disease remains defined clinically by its cardinal motor manifestations and pathologically by midbrain dopaminergic cell loss in association with Lewy bodies, it is now recognized that PD has substantially more widespread impact, causing a host of nonmotor symptoms and associated pathology in multiple regions throughout the nervous system. Further, the discovery and validation of PD-susceptibility genes contradict the historical view that environmental factors predominate, and blur distinctions between familial and sporadic disease. Genetic advances have also promoted the development of improved animal models, highlighted responsible molecular pathways, and revealed mechanistic overlap with other neurodegenerative disorders. In this review, we synthesize emerging lessons on PD pathogenesis from clinical, pathological, and genetic studies toward a unified concept of the disorder that may accelerate the design and testing of the next generation of PD therapies.

6 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 / Anonymous21571124 / 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.

7 Article Parkinson's disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms. 2019

Blauwendraat, Cornelis / Heilbron, Karl / Vallerga, Costanza L / Bandres-Ciga, Sara / von Coelln, Rainer / Pihlstrøm, Lasse / Simón-Sánchez, Javier / Schulte, Claudia / Sharma, Manu / Krohn, Lynne / Siitonen, Ari / Iwaki, Hirotaka / Leonard, Hampton / Noyce, Alastair J / Tan, Manuela / Gibbs, J Raphael / Hernandez, Dena G / Scholz, Sonja W / Jankovic, Joseph / Shulman, Lisa M / Lesage, Suzanne / Corvol, Jean-Christophe / Brice, Alexis / van Hilten, Jacobus J / Marinus, Johan / Anonymous861129 / Eerola-Rautio, Johanna / Tienari, Pentti / Majamaa, Kari / Toft, Mathias / Grosset, Donald G / Gasser, Thomas / Heutink, Peter / Shulman, Joshua M / Wood, Nicolas / Hardy, John / Morris, Huw R / Hinds, David A / Gratten, Jacob / Visscher, Peter M / Gan-Or, Ziv / Nalls, Mike A / Singleton, Andrew B / Anonymous871129. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · 23andMe, Inc., Mountain View, California, USA. · Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. · Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada. · Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. · Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland. · Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. · The Michael J Fox Foundation for Parkinson's Research, New York, New York, USA. · Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom. · Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom. · Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · Inserm U1127, Sorbonne Universités, UPMC Univ Paris 06 UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. · Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Neurology, Helsinki University Hospital, and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, United Kingdom. · Institute of Neuroscience & Psychology, University of Glasgow, Glasgow, United Kingdom. · Departments of Molecular & Human Genetics and Neuroscience, Baylor College of Medicine, Houston, Texas, USA. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA. · Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom. · Mater Research, Translational Research Institute, Brisbane, Queensland, Australia. · Queensland Brain Institute, The University of Queensland, Brisbane, Australia. · Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada. · Data Tecnica International, Glen Echo, Maryland, USA. ·Mov Disord · Pubmed #30957308.

ABSTRACT: BACKGROUND: Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. OBJECTIVES: To identify the genetic determinants of PD age at onset. METHODS: Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. RESULTS: We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. CONCLUSIONS: Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. © 2019 International Parkinson and Movement Disorder Society.

8 Article Emerging links between pediatric lysosomal storage diseases and adult parkinsonism. 2019

Ysselstein, Daniel / Shulman, Joshua M / Krainc, Dimitri. ·Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. · Departments of Neurology, Neuroscience, and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. · Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, Texas, USA. ·Mov Disord · Pubmed #30726573.

ABSTRACT: Lysosomal storage disorders comprise a clinically heterogeneous group of autosomal-recessive or X-linked genetic syndromes caused by disruption of lysosomal biogenesis or function resulting in accumulation of nondegraded substrates. Although lysosomal storage disorders are diagnosed predominantly in children, many show variable expressivity with clinical presentations possible later in life. Given the important role of lysosomes in neuronal homeostasis, neurological manifestations, including movement disorders, can accompany many lysosomal storage disorders. Over the last decade, evidence from genetics, clinical epidemiology, cell biology, and biochemistry have converged to implicate links between lysosomal storage disorders and adult-onset movement disorders. The strongest evidence comes from mutations in Glucocerebrosidase, which cause Gaucher's disease and are among the most common and potent risk factors for PD. However, recently, many additional lysosomal storage disorder genes have been similarly implicated, including SMPD1, ATP13A2, GALC, and others. Examination of these links can offer insight into pathogenesis of PD and guide development of new therapeutic strategies. We systematically review the emerging genetic links between lysosomal storage disorders and PD. © 2019 International Parkinson and Movement Disorder Society.

9 Article Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. 2017

Robak, Laurie A / Jansen, Iris E / van Rooij, Jeroen / Uitterlinden, André G / Kraaij, Robert / Jankovic, Joseph / Anonymous1541133 / Heutink, Peter / Shulman, Joshua M. ·Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX USA. · Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston TX USA. · German Center for Neurodegenerative Diseases (DZNE) and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany. · Department of Clinical Genetics, VU University Medical Center, Amsterdam 1081HZ, The Netherlands. · Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. · Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam, The Netherlands. · Department of Neurology, Erasmus MC, Rotterdam, The Netherlands. · Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. · Department of Neurology, Baylor College of Medicine, Houston, TX, USA. · Department of Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA. ·Brain · Pubmed #29140481.

ABSTRACT: Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility.

10 Article Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. 2017

Jansen, Iris E / Ye, Hui / Heetveld, Sasja / Lechler, Marie C / Michels, Helen / Seinstra, Renée I / Lubbe, Steven J / Drouet, Valérie / Lesage, Suzanne / Majounie, Elisa / Gibbs, J Raphael / Nalls, Mike A / Ryten, Mina / Botia, Juan A / Vandrovcova, Jana / Simon-Sanchez, Javier / Castillo-Lizardo, Melissa / Rizzu, Patrizia / Blauwendraat, Cornelis / Chouhan, Amit K / Li, Yarong / Yogi, Puja / Amin, Najaf / van Duijn, Cornelia M / Anonymous931133 / Morris, Huw R / Brice, Alexis / Singleton, Andrew B / David, Della C / Nollen, Ellen A / Jain, Shushant / Shulman, Joshua M / Heutink, Peter. ·German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany. · Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081HZ, The Netherlands. · Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. · Graduate School of Cellular & Molecular Neuroscience, Tübingen, 72074, Germany. · European Research Institute for the Biology of Aging, University of Groningen, University Medical Centre Groningen, Groningen, 9700AD, The Netherlands. · Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. · Northwestern University Feinberg School of Medicine, Ken and Ruth Davee Department of Neurology, Chicago, IL, USA. · Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière, Paris, France. · Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Department of Medical & Molecular Genetics, King's College London, London, UK. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · Department of Neurology, Baylor College of Medicine, Houston, TX, USA. · Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. · Assistance Publique Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France. · Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu. · Department of Neurology, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu. · Department of Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund St., N.1150, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu. · German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany. Peter.Heutink@dzne.de. · Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081HZ, The Netherlands. Peter.Heutink@dzne.de. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. Peter.Heutink@dzne.de. ·Genome Biol · Pubmed #28137300.

ABSTRACT: BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.

11 Article Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population. 2017

Giri, Anamika / Mok, Kin Y / Jansen, Iris / Sharma, Manu / Tesson, Christelle / Mangone, Graziella / Lesage, Suzanne / Bras, José M / Shulman, Joshua M / Sheerin, Una-Marie / Anonymous5870886 / Díez-Fairen, Mónica / Pastor, Pau / Martí, María José / Ezquerra, Mario / Tolosa, Eduardo / Correia-Guedes, Leonor / Ferreira, Joaquim / Amin, Najaf / van Duijn, Cornelia M / van Rooij, Jeroen / Uitterlinden, André G / Kraaij, Robert / Nalls, Michael / Simón-Sánchez, Javier. ·Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. · Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR S 1127, AP-HP, Pitié-Salpêtrière Hospital, Paris, France. · Departments of Neurology and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. · Movement Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain. · Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Barcelona, Spain; Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Department of Neurosciences, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal. · Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal. · Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands. · Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam, the Netherlands. · Department of Neurosciences, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal; Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam, the Netherlands. · Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam, the Netherlands. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. Electronic address: javier.simon-sanchez@dzne.de. ·Neurobiol Aging · Pubmed #27818000.

ABSTRACT: Mutations in TMEM230 have recently been associated to Parkinson's disease (PD). To further understand the role of this gene in the Caucasian population, we interrogated our large repository of next generation sequencing data from unrelated PD cases and controls, as well as multiplex families with autosomal dominant PD. We identified 2 heterozygous missense variants in 2 unrelated PD cases and not in our control database (p.Y106H and p.I162V), and a heterozygous missense variant in 2 PD cases from the same family (p.A163T). However, data presented herein is not sufficient to support the role of any of these variants in PD pathology. A series of unified sequence kernel association tests also failed to show a cumulative effect of rare variation in this gene on the risk of PD in the general Caucasian population. Further evaluation of genetic data from different populations is needed to understand the genetic role of TMEM230 in PD etiology.

12 Article The Role of MAPT Haplotype H2 and Isoform 1N/4R in Parkinsonism of Older Adults. 2016

Valenca, Guilherme T / Srivastava, Gyan P / Oliveira-Filho, Jamary / White, Charles C / Yu, Lei / Schneider, Julie A / Buchman, Aron S / Shulman, Joshua M / Bennett, David A / De Jager, Philip L. ·Movement Disorders Clinic, Roberto Santos General Hospital, Salvador, BA, Brazil. · Health Sciences Center, Federal University of Reconcavo of Bahia, Santo Antonio de Jesus, BA, Brazil. · Post-Graduate Program in Health Sciences, Federal University of Bahia, Salvador, BA, Brazil. · Program in Translational Neuropsychiatric Genomics, Departments of Neurology & Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, United States of America. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America. · Harvard Medical School, Boston, Massachusetts, United States of America. · Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America. · Departments of Neurology, Molecular and Human Genetics, and Neuroscience, and Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America. ·PLoS One · Pubmed #27458716.

ABSTRACT: BACKGROUND AND OBJECTIVE: Recently, we have shown that the Parkinson's disease (PD) susceptibility locus MAPT (microtubule associated protein tau) is associated with parkinsonism in older adults without a clinical diagnosis of PD. In this study, we investigated the relationship between parkinsonian signs and MAPT transcripts by assessing the effect of MAPT haplotypes on alternative splicing and expression levels of the most common isoforms in two prospective clinicopathologic studies of aging. MATERIALS AND METHODS: using regression analysis, controlling for age, sex, study and neuropathology, we evaluated 976 subjects with clinical, genotyping and brain pathology data for haplotype analysis. For transcript analysis, we obtained MAPT gene and isoform-level expression from the dorsolateral prefrontal cortex for 505 of these subjects. RESULTS: The MAPT H2 haplotype was associated with lower total MAPT expression (p = 1.2x10-14) and global parkinsonism at both study entry (p = 0.001) and proximate to death (p = 0.050). Specifically, haplotype H2 was primarily associated with bradykinesia in both assessments (p<0.001 and p = 0.008). MAPT total expression was associated with age and decreases linearly with advancing age (p<0.001). Analysing MAPT alternative splicing, the expression of 1N/4R isoform was inversely associated with global parkinsonism (p = 0.008) and bradykinesia (p = 0.008). Diminished 1N/4R isoform expression was also associated with H2 (p = 0.001). CONCLUSIONS: Overall, our results suggest that age and H2 are associated with higher parkinsonism score and decreased total MAPT RNA expression. Additionally, we found that H2 and parkinsonism are associated with altered expression levels of specific isoforms. These findings may contribute to the understanding of the association between MAPT locus and parkinsonism in elderly subjects and in some extent to age-related neurodegenerative diseases.

13 Article Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease. 2016

Chouhan, Amit K / Guo, Caiwei / Hsieh, Yi-Chen / Ye, Hui / Senturk, Mumine / Zuo, Zhongyuan / Li, Yarong / Chatterjee, Shreyasi / Botas, Juan / Jackson, George R / Bellen, Hugo J / Shulman, Joshua M. ·Department of Neurology, Baylor College of Medicine, Houston, TX, 77030, USA. · Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA. · Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. · Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA. · Department of Neurology, University of Texas Medical Branch, Galveston, TX, 77555, USA. · Parkinson's Disease Research, Education, and Clinical Center, Michael E. DeBakey VA Medical Center, Houston, TX, 77030, USA. · Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund Street, Suite N.1150, Houston, TX, 77030, USA. · Department of Neurology, Baylor College of Medicine, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu. · Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu. · Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu. · Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund Street, Suite N.1150, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu. ·Acta Neuropathol Commun · Pubmed #27338814.

ABSTRACT: Common neurodegenerative proteinopathies, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by the misfolding and aggregation of toxic protein species, including the amyloid beta (Aß) peptide, microtubule-associated protein Tau (Tau), and alpha-synuclein (αSyn) protein. These factors also show toxicity in Drosophila; however, potential limitations of prior studies include poor discrimination between effects on the adult versus developing nervous system and neuronal versus glial cell types. In addition, variable expression paradigms and outcomes hinder systematic comparison of toxicity profiles. Using standardized conditions and medium-throughput assays, we express human Tau, Aß or αSyn selectively in neurons of the adult Drosophila retina and monitor age-dependent changes in both structure and function, based on tissue histology and recordings of the electroretinogram (ERG), respectively. We find that each protein causes a unique profile of neurodegenerative pathology, demonstrating distinct and separable impacts on neuronal death and dysfunction. Strikingly, expression of Tau leads to progressive loss of ERG responses whereas retinal architecture and neuronal numbers are largely preserved. By contrast, Aß induces modest, age-dependent neuronal loss without degrading the retinal ERG. αSyn expression, using a codon-optimized transgene, is characterized by marked retinal vacuolar change, progressive photoreceptor cell death, and delayed-onset but modest ERG changes. Lastly, to address potential mechanisms, we perform transmission electron microscopy (TEM) to reveal potential degenerative changes at the ultrastructural level. Surprisingly, Tau and αSyn each cause prominent but distinct synaptotoxic profiles, including disorganization or enlargement of photoreceptor terminals, respectively. Our findings highlight variable and dynamic properties of neurodegeneration triggered by these disease-relevant proteins in vivo, and suggest that Drosophila may be useful for revealing determinants of neuronal dysfunction that precede cell loss, including synaptic changes, in the adult nervous system.

14 Article Association of Parkinson disease risk loci with mild parkinsonian signs in older persons. 2014

Shulman, Joshua M / Yu, Lei / Buchman, Aron S / Evans, Denis A / Schneider, Julie A / Bennett, David A / De Jager, Philip L. ·Department of Neurology, Baylor College of Medicine, Houston, Texas2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas3Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston. · Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois. · Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois. · Program in Translational Neuropsychiatric Genomics, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts7Harvard Medical School, Boston, Massachusetts8Program in Medical and Population Genetics, Broad Institute, Cam. ·JAMA Neurol · Pubmed #24514572.

ABSTRACT: IMPORTANCE: Parkinsonian motor signs are common in the aging population and are associated with adverse health outcomes. Compared with Parkinson disease (PD), potential genetic risk factors for mild parkinsonian signs have been largely unexplored. OBJECTIVE: To determine whether PD susceptibility loci are associated with parkinsonism or substantia nigra pathology in a large community-based cohort of older persons. DESIGN, SETTING, AND PARTICIPANTS: Eighteen candidate single-nucleotide polymorphisms from PD genome-wide association studies were evaluated in a joint clinicopathologic cohort. Participants included 1698 individuals and a nested autopsy collection of 821 brains from the Religious Orders Study and the Rush Memory and Aging Project, 2 prospective community-based studies. MAIN OUTCOMES AND MEASURES: The primary outcomes were a quantitative measure of global parkinsonism or component measures of bradykinesia, rigidity, tremor, and gait impairment that were based on the motor Unified Parkinson's Disease Rating Scale. In secondary analyses, we examined associations with additional quantitative motor traits and postmortem indices, including substantia nigra Lewy bodies and neuronal loss. RESULTS: Parkinson disease risk alleles in the MAPT (rs2942168; P = .0006) and CCDC62 (rs12817488; P = .004) loci were associated with global parkinsonism, and these associations remained after exclusion of patients with a PD diagnosis. Based on motor Unified Parkinson's Disease Rating Scale subscores, MAPT (P = .0002) and CCDC62 (P = .003) were predominantly associated with bradykinesia, and we further discovered associations between SREBF1 (rs11868035; P = .005) and gait impairment, SNCA (rs356220; P = .04) and rigidity, and GAK (rs1564282; P = .03) and tremor. In the autopsy cohort, only NMD3 (rs34016896; P = .03) was related to nigral neuronal loss, and no associations were detected with Lewy bodies. CONCLUSIONS AND RELEVANCE: In addition to the established link to PD susceptibility, our results support a broader role for several loci in the development of parkinsonian motor signs and nigral pathology in older persons.

15 Article Nigral pathology and parkinsonian signs in elders without Parkinson disease. 2012

Buchman, Aron S / Shulman, Joshua M / Nag, Sukriti / Leurgans, Sue E / Arnold, Steven E / Morris, Martha C / Schneider, Julie A / Bennett, David A. ·Rush Alzheimer's Disease Center, Chicago, IL, USA. Aron_S_Buchman@rush.edu ·Ann Neurol · Pubmed #22367997.

ABSTRACT: OBJECTIVE: Motor symptoms such as mild parkinsonian signs are common in older persons, but little is known about their underlying neuropathology. We tested the hypothesis that nigral pathology is related to parkinsonism in older persons without Parkinson disease (PD). METHODS: More than 2,500 persons participating in the Religious Orders Study or the Memory and Aging Project agreed to annual assessment of parkinsonism with a modified version of the Unified Parkinson Disease Rating Scale and brain donation. Brains from 744 deceased participants without PD were assessed for nigral neuronal loss and α-synuclein immunopositive Lewy bodies. RESULTS: Mean age at death was 88.5 years. Mean global parkinsonism was 18.6 (standard deviation, 11.90). About ⅓ of cases had mild or more severe nigral neuronal loss, and about 17% had Lewy bodies. In separate regression models that adjusted for age, sex, and education, nigral neuronal loss and Lewy bodies were both related to global parkinsonism (neuronal loss: estimate, 0.231; standard error [SE], 0.068; p < 0.001; Lewy bodies: estimate, 0.291; SE, 0.133; p = 0.029). Employing a similar regression model that included both measures, neuronal loss remained associated with global parkinsonism (neuronal loss: estimate, 0.206; SE, 0.075; p = 0.006). By contrast, the association between Lewy bodies and global parkinsonism was attenuated by >60% and was no longer significant (Lewy bodies: estimate, 0.112; SE, 0.148; p = 0.447), suggesting that neuronal loss may mediate the association of Lewy bodies with global parkinsonism. INTERPRETATION: Nigral pathology is common in persons without PD and may contribute to loss of motor function in old age.

16 Minor Reply: Lysosomal storage disorder gene variants in multiple system atrophy. 2018

Shulman, Joshua M. ·Departments of Neurology, Molecular and Human Genetics, and Neuroscience, Baylor College of Medicine, Houston, TX, USA. · Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX, USA. ·Brain · Pubmed #29741598.

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