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Parkinson Disease: HELP
Articles by John Hardy
Based on 82 articles published since 2010
(Why 82 articles?)
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Between 2010 and 2020, John Hardy wrote the following 82 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Review 199 years of Parkinson disease - what have we learned and what is the path to the future? 2016

Schulz, Jörg B / Hausmann, Laura / Hardy, John. ·Department of Neurology, University Hospital, RWTH Aachen University, Aachen, Germany. JNC-CE@ukaachen.de. · JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany. JNC-CE@ukaachen.de. · Department of Neurology, University Hospital, RWTH Aachen University, Aachen, Germany. · Reta Lila Weston Research Laboratories, UCL Institute of Neurology, Queen Square, London, WC1N3BG, UK. ·J Neurochem · Pubmed #27581372.

ABSTRACT: In 1817, 199 years ago, James Parkinson described for the first time in 'An Essay on the Shaking Palsy' the symptoms of the disease that was later named Parkinson Disease. The current special issue of the Journal of Neurochemistry is dedicated to the discoveries and advances that have been made since, leading to a better understanding of this neurodegenerative disease and of potential treatment options. Reputed researchers cover various aspects from neuroanatomical basics; genetic and molecular risk factors such as LRRK2; the available cell and animal models that mimic crucial features of the pathophysiology; to clinical aspects and treatments, including deep brain stimulation. This article is part of a special issue on Parkinson disease.

2 Review The Evolution of Genetics: Alzheimer's and Parkinson's Diseases. 2016

Singleton, Andrew / Hardy, John. ·Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA. Electronic address: singleta@mail.nih.gov. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA. ·Neuron · Pubmed #27311081.

ABSTRACT: Genetic discoveries underlie the majority of the current thinking in neurodegenerative disease. This work has been driven by the significant gains made in identifying causal mutations; however, the translation of genetic causes of disease into pathobiological understanding remains a challenge. The application of a second generation of genetics methods allows the dissection of moderate and mild genetic risk factors for disease. This requires new thinking in two key areas: what constitutes proof of pathogenicity, and how do we translate these findings to biological understanding. Here we describe the progress and ongoing evolution in genetics. We describe a view that rejects the tradition that genetic proof has to be absolute before functional characterization and centers on a multi-dimensional approach integrating genetics, reference data, and functional work. We also argue that these challenges cannot be efficiently met by traditional hypothesis-driven methods but that high content system-wide efforts are required.

3 Review Stem cell reprogramming: basic implications and future perspective for movement disorders. 2015

Brändl, Björn / Schneider, Susanne A / Loring, Jeanne F / Hardy, John / Gribbon, Philip / Müller, Franz-Josef. ·Center for Psychiatry, University Hospital Schleswig Holstein, Campus Kiel, Germany. ·Mov Disord · Pubmed #25546831.

ABSTRACT: The introduction of stem cell-associated molecular factors into human patient-derived cells allows for their reprogramming in the laboratory environment. As a result, human induced pluripotent stem cells (hiPSC) can now be reprogrammed epigenetically without disruption of their overall genomic integrity. For patients with neurodegenerative diseases characterized by progressive loss of functional neurons, the ability to reprogram any individual's cells and drive their differentiation toward susceptible neuronal subtypes holds great promise. Apart from applications in regenerative medicine and cell replacement-based therapy, hiPSCs are increasingly used in preclinical research for establishing disease models and screening for drug toxicities. The rapid developments in this field prompted us to review recent progress toward the applications of stem cell technologies for movement disorders. We introduce reprogramming strategies and explain the critical steps in the differentiation of hiPSCs to clinical relevant subtypes of cells in the context of movement disorders. We summarize and discuss recent discoveries in this field, which, based on the rapidly expanding basic science literature as well as upcoming trends in personalized medicine, will strongly influence the future therapeutic options available to practitioners working with patients suffering from such disorders.

4 Review Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease. 2014

Berg, Daniela / Postuma, Ronald B / Bloem, Bastiaan / Chan, Piu / Dubois, Bruno / Gasser, Thomas / Goetz, Christopher G / Halliday, Glenda M / Hardy, John / Lang, Anthony E / Litvan, Irene / Marek, Kenneth / Obeso, José / Oertel, Wolfgang / Olanow, C Warren / Poewe, Werner / Stern, Matthew / Deuschl, Günther. ·Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center of Neurodegenerative Diseases, Tuebingen, Germany. ·Mov Disord · Pubmed #24619848.

ABSTRACT: With advances in knowledge disease, boundaries may change. Occasionally, these changes are of such a magnitude that they require redefinition of the disease. In recognition of the profound changes in our understanding of Parkinson's disease (PD), the International Parkinson and Movement Disorders Society (MDS) commissioned a task force to consider a redefinition of PD. This review is a discussion article, intended as the introductory statement of the task force. Several critical issues were identified that challenge current PD definitions. First, new findings challenge the central role of the classical pathologic criteria as the arbiter of diagnosis, notably genetic cases without synuclein deposition, the high prevalence of incidental Lewy body (LB) deposition, and the nonmotor prodrome of PD. It remains unclear, however, whether these challenges merit a change in the pathologic gold standard, especially considering the limitations of alternate gold standards. Second, the increasing recognition of dementia in PD challenges the distinction between diffuse LB disease and PD. Consideration might be given to removing dementia as an exclusion criterion for PD diagnosis. Third, there is increasing recognition of disease heterogeneity, suggesting that PD subtypes should be formally identified; however, current subtype classifications may not be sufficiently robust to warrant formal delineation. Fourth, the recognition of a nonmotor prodrome of PD requires that new diagnostic criteria for early-stage and prodromal PD should be created; here, essential features of these criteria are proposed. Finally, there is a need to create new MDS diagnostic criteria that take these changes in disease definition into consideration.

5 Review Parkinson's disease--the debate on the clinical phenomenology, aetiology, pathology and pathogenesis. 2013

Jenner, Peter / Morris, Huw R / Robbins, Trevor W / Goedert, Michel / Hardy, John / Ben-Shlomo, Yoav / Bolam, Paul / Burn, David / Hindle, John V / Brooks, David. ·Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King's College, London, UK. peter.jenner@kcl.ac.uk ·J Parkinsons Dis · Pubmed #23938306.

ABSTRACT: The definition of Parkinson's disease (PD) is changing with the expansion of clinical phenomenology and improved understanding of environmental and genetic influences that impact on the pathogenesis of the disease at the cellular and molecular level. This had led to debate and discussion with as yet, no general acceptance of the direction that change should take either at the level of diagnosis or of what should and should not be sheltered under an umbrella of PD. This article is one contribution to this on-going discussion. There are two different themes running through the article--widening the definition of PD/LBD/synucleinopathies and the heterogeneity that exists within PD itself from a clinical, pathological and genetic perspective. The conclusion reached is that in the future, further diagnostic categories will need to be recognized. These are likely to include--Parkinson's syndrome, Parkinson's syndrome likely to be Lewy body PD, clinical PD (defined by QSBB criteria), Lewy body disease (PD, LBD, REM SBD) and synucleinopathies (including LBD, MSA).

6 Review TDP-43 pathology in a patient carrying G2019S LRRK2 mutation and a novel p.Q124E MAPT. 2013

Ling, Helen / Kara, Eleanna / Bandopadhyay, Rina / Hardy, John / Holton, Janice / Xiromerisiou, Georgia / Lees, Andrew / Houlden, Henry / Revesz, Tamas. ·Reta Lila Weston Institute of Neurological Studies and Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK. ·Neurobiol Aging · Pubmed #23664753.

ABSTRACT: Leucine-rich repeat kinase 2 (LRRK2) mutation is the most common cause of genetic-related parkinsonism and is usually associated with Lewy body pathology; however, tau, α-synuclein, and ubiquitin pathologies have also been reported. We report the case of a patient carrying the LRRK2 G2019S mutation and a novel heterozygous variant c.370C>G, p.Q124E in exon 4 of the microtubule-associated protein tau (MAPT). The patient developed parkinsonism with good levodopa response in her 70s. Neuropathological analysis revealed nigral degeneration and Alzheimer-type tau pathology without Lewy bodies. Immunohistochemical staining using phospho-TDP-43 antibodies identified occasional TDP-43 pathology in the hippocampus, temporal neocortex, striatum, and substantia nigra. However, TDP-43 pathology was not identified in another 4 archival LRRK2 G2019S cases with Lewy body pathology available in the Queen Square Brain Bank. Among other published cases of patients carrying LRRK2 G2019S mutation, only 3 were reportedly evaluated for TDP-43 pathology, and the results were negative. The role of the MAPT variant in the clinical and pathological manifestation in LRRK2 cases remains to be determined.

7 Review Parkinson's disease and α-synuclein expression. 2011

Devine, Michael J / Gwinn, Katrina / Singleton, Andrew / Hardy, John. ·Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK. m.devine@ion.ucl.ac.uk ·Mov Disord · Pubmed #21887711.

ABSTRACT: Genetic studies of Parkinson's disease over the last decade or more have revolutionized our understanding of this condition. α-Synuclein was the first gene to be linked to Parkinson's disease, and is arguably the most important: the protein is the principal constituent of Lewy bodies, and variation at its locus is the major genetic risk factor for sporadic disease. Intriguingly, duplications and triplications of the locus, as well as point mutations, cause familial disease. Therefore, subtle alterations of α-synuclein expression can manifest with a dramatic phenotype. We outline the clinical impact of α-synuclein locus multiplications, and the implications that this has for Parkinson's disease pathogenesis. Finally, we discuss potential strategies for disease-modifying therapies for this currently incurable disorder.

8 Review Milestones in PD genetics. 2011

Gasser, Thomas / Hardy, John / Mizuno, Yoshikuni. ·Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, and German Center for Neurodegenerative Diseases, Tübingen, Germany. Thomas.Gasser@uni-tuebingen.de ·Mov Disord · Pubmed #21626549.

ABSTRACT: Over the last 25 years, genetic findings have profoundly changed our views on the etiology of Parkinson's disease. Linkage studies and positional cloning strategies have identified mutations in a number of genes that cause several monogenic autosomal-dominant or autosomal-recessive forms of the disorder. Although most of these Mendelian forms of Parkinson's disease are rare, whole-genome association studies have more recently provided convincing evidence that low-penetrance variants in at least some of these, but also in several other genes, play a direct role in the etiology of the common sporadic disease as well. In addition, rare variants with intermediate-effect strengths in genes such as Gaucher's disease-associated glucocerebrosidase A have been discovered as important risk factors. "Next-generation" sequencing technologies are expected by some to identify many more of these variants. Thus, an increasingly complex network of genes contributing in different ways to disease risk and progression is emerging. These findings may provide the "genetic entry points" to identify molecular targets and readouts necessary to design rational disease-modifying treatments.

9 Review Genetic analysis of pathways to Parkinson disease. 2010

Hardy, John. ·Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. j.hardy@ion.ucl.ac.uk ·Neuron · Pubmed #20955928.

ABSTRACT: In this review I outline the arguments as to whether we should consider Parkinson disease one or more than one entity and discuss genetic findings from Mendelian and whole-genome association analysis in that context. I discuss what the demonstration of disease spread implies for our analysis of the genetic and epidemiologic risk factors for disease and outline the surprising fact that we now have genetically identified on the order of half our risk for developing the disease.

10 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.

11 Article Failures in Protein Clearance Partly Underlie Late Onset Neurodegenerative Diseases and Link Pathology to Genetic Risk. 2019

Hardy, John. ·Department of Neurodegenerative Disease and Reta Lila Weston Laboratories, UCL Queen Square Institute of Neurology, London, United Kingdom. · UK Dementia Research Institute, UCL Queen Square Institute of Neurology, London, United Kingdom. ·Front Neurosci · Pubmed #31866813.

ABSTRACT: As we identify the loci involved in late onset neurodegenerative disease, we are finding that the majority of them are involved in damage response processes. In this short review, I propose that it is partly a failure in these damage response processes which underlie late onset disease and that the resultant pathology is a marker of the type of damage response which has failed: microglial clearance of damaged neuronal membranes in Alzheimer's disease (AD), ubiquitin proteasome clearance in the tauopathies, and lysosomal clearance in Parkinson's disease (PD). In this review, I outline this relationship. This article is not intended as a comprehensive review of the cell biology of any of these disorders but rather a summary of the evidence that the genetics and pathology of these disorders appear to point, in each case, to the removal of misfolded proteins as a critical process in disease pathogenesis.

12 Article The Parkinson's Disease Mendelian Randomization Research Portal. 2019

Noyce, Alastair J / Bandres-Ciga, Sara / Kim, Jonggeol / Heilbron, Karl / Kia, Demis / Hemani, Gibran / Xue, Angli / Lawlor, Debbie A / Smith, George Davey / Duran, Raquel / Gan-Or, Ziv / Blauwendraat, Cornelis / Gibbs, J Raphael / Anonymous7311119 / Hinds, David A / Yang, Jian / Visscher, Peter / Cuzick, Jack / Morris, Huw / Hardy, John / Wood, Nicholas W / Nalls, Mike A / Singleton, Andrew B. ·Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom. · Department of Clinical and Movement Neurosciences, University College London, Institute of Neurology, London, United Kingdom. · Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain. · 23andMe, Inc., Mountain View, California, USA. · MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom. · Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. · Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. · Population Health Science, Bristol Medical School, University of Bristol, Bristol, United Kingdom. · Centro de Investigacion Biomedica and Departamento de Fisiologia, Facultad de Medicina, Universidad de Granada, Granada, Spain. · Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada. · Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada. · Institute for Advanced Research, Wenzhou Medical University, Wenzhou, Zhejiang, China. · Data Tecnica International, Glen Echo, Maryland, USA. ·Mov Disord · Pubmed #31659794.

ABSTRACT: BACKGROUND: Mendelian randomization is a method for exploring observational associations to find evidence of causality. OBJECTIVE: To apply Mendelian randomization between risk factors/phenotypic traits (exposures) and PD in a large, unbiased manner, and to create a public resource for research. METHODS: We used two-sample Mendelian randomization in which the summary statistics relating to single-nucleotide polymorphisms from 5,839 genome-wide association studies of exposures were used to assess causal relationships with PD. We selected the highest-quality exposure genome-wide association studies for this report (n = 401). For the disease outcome, summary statistics from the largest published PD genome-wide association studies were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted method, followed by a range of sensitivity analyses. We used a false discovery rate of 5% from the inverse variance weighted analysis to prioritize exposures of interest. RESULTS: We observed evidence for causal associations between 12 exposures and risk of PD. Of these, nine were effects related to increasing adiposity and decreasing risk of PD. The remaining top three exposures that affected PD risk were tea drinking, time spent watching television, and forced vital capacity, but these may have been biased and were less convincing. Other exposures at nominal statistical significance included inverse effects of smoking and alcohol. CONCLUSIONS: We present a new platform which offers Mendelian randomization analyses for a total of 5,839 genome-wide association studies versus the largest PD genome-wide association studies available (https://pdgenetics.shinyapps.io/MRportal/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

13 Article Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer's and Parkinson's disease. 2019

Sjödin, Simon / Brinkmalm, Gunnar / Öhrfelt, Annika / Parnetti, Lucilla / Paciotti, Silvia / Hansson, Oskar / Hardy, John / Blennow, Kaj / Zetterberg, Henrik / Brinkmalm, Ann. ·Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, House V3, SU/Mölndal, SE-43180, Mölndal, Sweden. simon.sjodin@neuro.gu.se. · Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. simon.sjodin@neuro.gu.se. · Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, House V3, SU/Mölndal, SE-43180, Mölndal, Sweden. · Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. · Laboratory of Clinical Neurochemistry, Neurology Clinic, University of Perugia, Perugia, Italy. · Department of Experimental Medicine, University of Perugia, Perugia, Italy. · Laboratory of Clinical Neurochemistry, Department of Medicine, University of Perugia, Perugia, Italy. · Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden. · Memory Clinic, Skåne University Hospital, Malmö, Sweden. · Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London, UK. · UK Dementia Research Institute at UCL, London, UK. ·Alzheimers Res Ther · Pubmed #31521194.

ABSTRACT: BACKGROUND: Increasing evidence implicates dysfunctional proteostasis and the involvement of the autophagic and endo-lysosomal system and the ubiquitin-proteasome system in neurodegenerative diseases. In Alzheimer's disease (AD), there is an accumulation of autophagic vacuoles within the neurons. In Parkinson's disease (PD), susceptibility has been linked to genes encoding proteins involved in autophagy and lysosomal function, as well as mutations causing lysosomal disorders. Furthermore, both diseases are characterized by the accumulation of protein aggregates. METHODS: Proteins associated with endocytosis, lysosomal function, and the ubiquitin-proteasome system were identified in the cerebrospinal fluid (CSF) and targeted by combining solid-phase extraction and parallel reaction monitoring mass spectrometry. In total, 50 peptides from 18 proteins were quantified in three cross-sectional cohorts including AD (N = 61), PD (N = 21), prodromal AD (N = 10), stable mild cognitive impairment (N = 15), and controls (N = 68). RESULTS: A pilot study, including subjects selected based on their AD CSF core biomarker concentrations, showed increased concentrations of several targeted proteins in subjects with core biomarker levels indicating AD pathology compared to controls. Next, in a clinically characterized cohort, lower concentrations in CSF of proteins in PD were found compared to subjects with prodromal AD. Further investigation in an additional clinical study again revealed lower concentrations in CSF of proteins in PD compared to controls and AD. CONCLUSION: In summary, significantly different peptide CSF concentrations were identified from proteins AP2B1, C9, CTSB, CTSF, GM2A, LAMP1, LAMP2, TCN2, and ubiquitin. Proteins found to have altered concentrations in more than one study were AP2B1, CTSB, CTSF, GM2A, LAMP2, and ubiquitin. Interestingly, given the genetic implication of lysosomal function in PD, we did identify the CSF concentrations of CTSB, CTSF, GM2A, and LAMP2 to be altered. However, we also found differences in proteins associated with endocytosis (AP2B1) and the ubiquitin-proteasome system (ubiquitin). No difference in any peptide CSF concentration was found in clinically characterized subjects with AD compared to controls. In conclusion, CSF analyses of subjects with PD suggest a general lysosomal dysfunction, which resonates well with recent genetic findings, while such changes are minor or absent in AD.

14 Article Genetic analysis of Mendelian mutations in a large UK population-based Parkinson's disease study. 2019

Tan, Manuela M X / Malek, Naveed / Lawton, Michael A / Hubbard, Leon / Pittman, Alan M / Joseph, Theresita / Hehir, Jason / Swallow, Diane M A / Grosset, Katherine A / Marrinan, Sarah L / Bajaj, Nin / Barker, Roger A / Burn, David J / Bresner, Catherine / Foltynie, Thomas / Hardy, John / Wood, Nicholas / Ben-Shlomo, Yoav / Grosset, Donald G / Williams, Nigel M / Morris, Huw R. ·Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. · UCL Movement Disorders Centre, University College London, London, UK. · Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK. · Population Health Sciences, University of Bristol, UK. · Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. · University College London Hospitals NHS Foundation Trust, UK. · Institute of Neuroscience, University of Newcastle, Newcastle upon Tyne, UK. · Department of Clinical Neurosciences, University of Nottingham, UK. · Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge UK. · Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, Cambridge, UK. · Reta Lila Weston Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. ·Brain · Pubmed #31324919.

ABSTRACT: Our objective was to define the prevalence and clinical features of genetic Parkinson's disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson's Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson's study, 424 had young-onset Parkinson's disease (age at onset ≤ 50) and 1799 had late onset Parkinson's disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 'Kompetitive' allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson's disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson's disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors.

15 Article L-dopa responsiveness in early Parkinson's disease is associated with the rate of motor progression. 2019

Malek, Naveed / Kanavou, Sofia / Lawton, Michael A / Pitz, Vanessa / Grosset, Katherine A / Bajaj, Nin / Barker, Roger A / Ben-Shlomo, Yoav / Burn, David J / Foltynie, Tom / Hardy, John / Williams, Nigel M / Wood, Nicholas / Morris, Huw R / Grosset, Donald G / Anonymous9101121. ·Department of Neurology, East Suffolk and North Essex NHS Foundation Trust, Ipswich, UK. Electronic address: nmalek@nhs.net. · School of Social and Community Medicine, University of Bristol, Bristol, UK. · Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK. · Department of Neurology, University of Nottingham, UK. · Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, Cambridge, UK. · Faculty of Medical Sciences, University of Newcastle, Newcastle upon Tyne, UK. · Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, London, UK. · Reta Lila Weston Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. ·Parkinsonism Relat Disord · Pubmed #31105012.

ABSTRACT: BACKGROUND: L-dopa responsiveness in Parkinson's disease (PD) varies, but the clinical correlates and significance of this are ill-defined. METHODS: Patients were assessed before and after their usual morning L-dopa dose, using the MDS Unified PD Rating Scale Part 3 (MDS UPDRS 3), and rated as definite responders (≥24.5% improvement) or limited responders (<24.5%). RESULTS: 1007 cases, mean age 66.1 years (SD 9.1) at diagnosis, were assessed 3.4 (SD 0.9) years after diagnosis. The L-dopa response was definite in 614 cases (61.0%), median reduction in MDS UPDRS 3 scores was 42.0%, (IQR 33.3, 53.1), and was limited in 393 cases (39.0%), median reduction in MDS UPDRS 3 scores 11.5% (IQR 4.3, 18.2). Definite responders were younger (66.3 years at study entry, SD 9.3) than limited responders (69.2 years, SD 8.4, p < 0.001). The MDS UPDRS 3 score at study entry in definite responders (21.0, SD 10.5) was significantly lower than in limited responders (24.7, SD 13.4, p < 0.001). The MDS UPDRS 3 increase over 18 months was less in definite responders at 3.0 (SD 10.4), compared to limited responders (6.4, SD 11.0, p < 0.001). The levodopa equivalent daily dose (LEDD) was not significantly different at study entry (definite responders 317 mg, SD 199, vs limited responders 305 mg, SD 191, p = 0.53). However, LEDD was significantly higher at the time of the L-dopa challenge test in definite responders (541 mg, SD 293) compared to limited responders (485 mg, SD 215, p = 0.01). Responsiveness to L-dopa was unaffected by the challenge test dose (p = 0.54). CONCLUSIONS: The main determinants of variation in the L-dopa response in early PD are age and motor severity. A limited L-dopa response is associated with faster motor progression.

16 Article Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability. 2019

Reynolds, Regina H / Botía, Juan / Nalls, Mike A / Anonymous4111133 / Anonymous4121133 / Hardy, John / Gagliano Taliun, Sarah A / Ryten, Mina. ·1Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, UK. · 0000000121901201 · grid.83440.3b · 2Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Murcia, Spain. · 0000 0001 2287 8496 · grid.10586.3a · 3Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland USA. · 0000 0001 2297 5165 · grid.94365.3d · Data Tecnica International, Glen Echo, Maryland USA. · 5UK Dementia Research Institute at University College London (UCL), London, UK. · 6Center for Statistical Genetics and Department of Biostatistics, University of Michigan, Ann Arbor, Michigan USA. · 0000000086837370 · grid.214458.e ·NPJ Parkinsons Dis · Pubmed #31016231.

ABSTRACT: Parkinson's disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.

17 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.

18 Article Insights into the Influence of Specific Splicing Events on the Structural Organization of 2018

Vlachakis, Dimitrios / Labrou, Nikolaos E / Iliopoulos, Costas / Hardy, John / Lewis, Patrick A / Rideout, Hardy / Trabzuni, Daniah. ·Genetics Laboratory, Department of Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, 11855 Athens, Greece. dimvl@aua.gr. · Laboratory of Enzyme Technology, Department of Biotechnology, School of Food, Biotechnology and Development, Agricultural University of Athens, 75 Iera Odos Street, 11855 Athens, Greece. lambrou@aua.gr. · Department of Informatics, Faculty of Natural and Mathematical Sciences, King's College London, Strand, London WC2R 2LS, UK. csi@kcl.ac.uk. · Department of Neurodegenerative disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. j.hardy@ucl.ac.uk. · Department of Neurodegenerative disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. p.a.lewis@reading.ac.uk. · School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AP, UK. p.a.lewis@reading.ac.uk. · Division of Basic Neurosciences; Biomedical Research Foundation of the Academy of Athens, Soranou Efessiou 4, 11527 Athens, Greece. hrideout@bioacademy.gr. · Department of Neurodegenerative disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. d.trabzuni@ucl.ac.uk. · Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia. d.trabzuni@ucl.ac.uk. ·Int J Mol Sci · Pubmed #30223621.

ABSTRACT: Leucine-rich repeat kinase 2 (LRRK2) is a large protein of unclear function. Rare mutations in the

19 Article Stratification of candidate genes for Parkinson's disease using weighted protein-protein interaction network analysis. 2018

Ferrari, Raffaele / Kia, Demis A / Tomkins, James E / Hardy, John / Wood, Nicholas W / Lovering, Ruth C / Lewis, Patrick A / Manzoni, Claudia. ·Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1B 5EH, UK. · School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AP, UK. · Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, WC1E 6JF, UK. · Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1B 5EH, UK. c.manzoni@reading.ac.uk. · School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AP, UK. c.manzoni@reading.ac.uk. ·BMC Genomics · Pubmed #29898659.

ABSTRACT: BACKGROUND: Genome wide association studies (GWAS) have helped identify large numbers of genetic loci that significantly associate with increased risk of developing diseases. However, translating genetic knowledge into understanding of the molecular mechanisms underpinning disease (i.e. disease-specific impacted biological processes) has to date proved to be a major challenge. This is primarily due to difficulties in confidently defining candidate genes at GWAS-risk loci. The goal of this study was to better characterize candidate genes within GWAS loci using a protein interactome based approach and with Parkinson's disease (PD) data as a test case. RESULTS: We applied a recently developed Weighted Protein-Protein Interaction Network Analysis (WPPINA) pipeline as a means to define impacted biological processes, risk pathways and therein key functional players. We used previously established Mendelian forms of PD to identify seed proteins, and to construct a protein network for genetic Parkinson's and carried out functional enrichment analyses. We isolated PD-specific processes indicating 'mitochondria stressors mediated cell death', 'immune response and signaling', and 'waste disposal' mediated through 'autophagy'. Merging the resulting protein network with data from Parkinson's GWAS we confirmed 10 candidate genes previously selected by pure proximity and were able to nominate 17 novel candidate genes for sporadic PD. CONCLUSIONS: With this study, we were able to better characterize the underlying genetic and functional architecture of idiopathic PD, thus validating WPPINA as a robust pipeline for the in silico genetic and functional dissection of complex disorders.

20 Article Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum. 2018

Karch, Celeste M / Wen, Natalie / Fan, Chun C / Yokoyama, Jennifer S / Kouri, Naomi / Ross, Owen A / Höglinger, Gunter / Müller, Ulrich / Ferrari, Raffaele / Hardy, John / Schellenberg, Gerard D / Sleiman, Patrick M / Momeni, Parastoo / Hess, Christopher P / Miller, Bruce L / Sharma, Manu / Van Deerlin, Vivianna / Smeland, Olav B / Andreassen, Ole A / Dale, Anders M / Desikan, Rahul S / Anonymous8800942. ·Department of Psychiatry, Washington University in St Louis, St Louis, Missouri. · Department of Cognitive Sciences, University of California, San Diego, La Jolla. · Memory and Aging Center, Department of Neurology, University of California, San Francisco. · Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida. · Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases, Munich, Germany. · Department of Neurology, Technical University of Munich, Munich Cluster for Systems Neurology SyNergy, Munich, Germany. · Institut for Humangenetik, Justus-Liebig-Universität, Giessen, Germany. · Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom. · Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. · Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. · Division of Human Genetics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. · Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia. · Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock. · Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. · Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. · Department of Neurosciences, University of California, San Diego, La Jolla. · Department of Neurosciences and Radiology, University of California, San Diego, La Jolla. ·JAMA Neurol · Pubmed #29630712.

ABSTRACT: Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood. Objectives: To examine whether there are common genetic variants that determine the risk for ALS and other neurodegenerative diseases and to identify their functional pathways. Design, Setting, and Participants: In this study conducted from December 1, 2016, to August 1, 2017, the genetic overlap between ALS, sporadic frontotemporal dementia (FTD), FTD with TDP-43 inclusions, Parkinson disease (PD), Alzheimer disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) were systematically investigated in 124 876 cases and controls. No participants were excluded from this study. Diagnoses were established using consensus criteria. Main Outcomes and Measures: The primary outcomes were a list of novel loci and their functional pathways in ALS, FTD, PSP, and ALS mouse models. Results: Among 124 876 cases and controls, genome-wide conjunction analyses of ALS, FTD, PD, AD, CBD, and PSP revealed significant genetic overlap between ALS and FTD at known ALS loci: rs13302855 and rs3849942 (nearest gene, C9orf72; P = .03 for rs13302855 and P = .005 for rs3849942) and rs4239633 (nearest gene, UNC13A; P = .03). Significant genetic overlap was also found between ALS and PSP at rs7224296, which tags the MAPT H1 haplotype (nearest gene, NSF; P = .045). Shared risk genes were enriched for pathways involving neuronal function and development. At a conditional FDR P < .05, 22 novel ALS polymorphisms were found, including rs538622 (nearest gene, ERGIC1; P = .03 for ALS and FTD), which modifies BNIP1 expression in human brains (35 of 137 females; mean age, 59 years; P = .001). BNIP1 expression was significantly reduced in spinal cord motor neurons from patients with ALS (4 controls: mean age, 60.5 years, mean [SE] value, 3984 [760.8] arbitrary units [AU]; 7 patients with ALS: mean age, 56 years, mean [SE] value, 1999 [274.1] AU; P = .02), in an ALS mouse model (mean [SE] value, 13.75 [0.09] AU for 2 SOD1 WT mice and 11.45 [0.03] AU for 2 SOD1 G93A mice; P = .002) and in brains of patients with PSP (80 controls: 39 females; mean age, 82 years, mean [SE] value, 6.8 [0.2] AU; 84 patients with PSP: 33 females, mean age 74 years, mean [SE] value, 6.8 [0.1] AU; β = -0.19; P = .009) or FTD (11 controls: 4 females; mean age, 67 years; mean [SE] value, 6.74 [0.05] AU; 17 patients with FTD: 10 females; mean age, 69 years; mean [SE] value, 6.53 [0.04] AU; P = .005). Conclusions and Relevance: This study found novel genetic overlap between ALS and diseases of the FTD spectrum, that the MAPT H1 haplotype confers risk for ALS, and identified the mitophagy-associated, proapoptotic protein BNIP1 as an ALS risk gene. Together, these findings suggest that sporadic ALS may represent a selectively pleiotropic, polygenic disorder.

21 Article mTOR independent alteration in ULK1 Ser758 phosphorylation following chronic LRRK2 kinase inhibition. 2018

Manzoni, Claudia / Mamais, Adamantios / Dihanich, Sybille / Soutar, Marc P M / Plun-Favreau, Helene / Bandopadhyay, Rina / Abeti, Rosella / Giunti, Paola / Hardy, John / R Cookson, Mark / Tooze, Sharon A / Lewis, Patrick A. ·School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AP, U.K. c.manzoni@reading.ac.uk. · Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, U.K. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A. · Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, 1 Wakefield Street London WC1N 1PJ, U.K. · Department of Molecular Neuroscience, UCL Institute of Neurology, Ataxia Centre, Queen Square, London WC1N 3BG, United Kingdom. · The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, U.K. · School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AP, U.K. ·Biosci Rep · Pubmed #29563162.

ABSTRACT: Unc-51 Like Kinase 1 (ULK1) is a critical regulator of the biogenesis of autophagosomes, the central component of the catabolic macroautophagy pathway. Regulation of ULK1 activity is dependent upon several phosphorylation events acting to repress or activate the enzymatic function of this protein. Phosphorylation of Ser758 ULK1 has been linked to repression of autophagosome biogenesis and was thought to be exclusively dependent upon mTOR complex 1 kinase activity. In the present study, a novel regulation of Ser758 ULK1 phosphorylation is reported following prolonged inhibition of the Parkinson's disease linked protein leucine rich repeat kinase 2 (LRRK2). Here, modulation of Ser758 ULK1 phosphorylation following LRRK2 inhibition is decoupled from the repression of autophagosome biogenesis and independent of mTOR complex 1 activity.

22 Article Features of 2018

Malek, Naveed / Weil, Rimona S / Bresner, Catherine / Lawton, Michael A / Grosset, Katherine A / Tan, Manuela / Bajaj, Nin / Barker, Roger A / Burn, David J / Foltynie, Thomas / Hardy, John / Wood, Nicholas W / Ben-Shlomo, Yoav / Williams, Nigel W / Grosset, Donald G / Morris, Huw R / Anonymous661112. ·Department of Neurology, Ipswich Hospital NHS Trust, Ipswich, UK. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. · School of Social and Community Medicine, University of Bristol, Bristol, UK. · Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, Scotland. · Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. · Department of Neurology, Queen's Medical Centre, Nottingham, UK. · Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, Cambridge, UK. · Faculty of Medical Sciences, University of Newcastle, Newcastle upon Tyne, UK. · Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, UK. · Department of Molecular Neuroscience, Reta Lila Weston Laboratories, UCL Institute of Neurology, London, UK. ·J Neurol Neurosurg Psychiatry · Pubmed #29378790.

ABSTRACT: OBJECTIVES: To examine the influence of the glucocerebrosidase ( METHODS: We prospectively recruited patients with PD in the RESULTS: We studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher's disease (GD) causing pathogenic mutations; 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the CONCLUSIONS: Our study confirms the influence of CLINICAL TRIAL REGISTRATION: NCT02881099; Results.

23 Article Autonomic Dysfunction in Early Parkinson's Disease: Results from the United Kingdom Tracking Parkinson's Study. 2017

Malek, Naveed / Lawton, Michael A / Grosset, Katherine A / Bajaj, Nin / Barker, Roger A / Burn, David J / Foltynie, Tom / Hardy, John / Morris, Huw R / Williams, Nigel M / Ben-Shlomo, Yoav / Wood, Nicholas W / Grosset, Donald G / Anonymous5440966. ·Department of Neurology Ipswich Hospital NHS Trust Ipswich United Kingdom. · School of Social and Community Medicine University of Bristol Bristol United Kingdom. · Institute of Neurological Sciences Queen Elizabeth University Hospital Glasgow United Kingdom. · Department of Neurology Queen's Medical Centre Nottingham United Kingdom. · Department of Clinical Neurosciences John van Geest Centre for Brain Repair Cambridge United Kingdom. · Institute of Neuroscience University of Newcastle Newcastle upon Tyne United Kingdom. · Sobell Department of Motor Neuroscience UCL Institute of Neurology London United Kingdom. · Reta Lila Weston Laboratories Department of Molecular Neuroscience UCL Institute of Neurology London United Kingdom. · Department of Clinical Neuroscience UCL Institute of Neurology London United Kingdom. · Institute of Psychological Medicine and Clinical Neurosciences MRC Centre for Neuropsychiatric Genetics and Genomics Cardiff University Cardiff United Kingdom. · Department of Molecular Neuroscience UCL Institute of Neurology London United Kingdom. ·Mov Disord Clin Pract · Pubmed #30363477.

ABSTRACT: Background: Autonomic dysfunction is common in the later stages of Parkinson's disease (PD), but less is known about its presence and severity in early disease. Objective: To analyze features of autonomic dysfunction in recent onset PD cases, and their relationship to motor severity, medication use, other nonmotor symptoms (NMS), and quality-of-life scores. Methods: Detailed patient-reported symptoms of autonomic dysfunction were assessed in a multicenter cohort study in PD cases that had been diagnosed within the preceding 3.5 years. Results: There were 1746 patients (1132 males, 65.2%), mean age 67.6 years (SD 9.3), mean disease duration 1.3 years (SD 0.9), mean Movement Disorder Society Unified Parkinson's Disease Rating Scale motor score 22.5 (SD 12.1). Orthostatic symptoms were reported by 39.6%, male erectile dysfunction by 56.1%, and female anorgasmia by 57.4%. Sialorrhea was an issue in 51.4% of patients, constipation in 43.6%, and dysphagia in 20.1%. Autonomic features increased with higher modified Hoehn and Yahr stages ( Conclusions: Autonomic dysfunction is common in early PD. Autonomic dysfunction correlates with the presence of other NMS, and with worse quality of life.

24 Article Establishing the role of rare coding variants in known Parkinson's disease risk loci. 2017

Jansen, Iris E / Gibbs, J Raphael / Nalls, Mike A / Price, T Ryan / Lubbe, Steven / van Rooij, Jeroen / Uitterlinden, André G / Kraaij, Robert / Williams, Nigel M / Brice, Alexis / Hardy, John / Wood, Nicholas W / Morris, Huw R / Gasser, Thomas / Singleton, Andrew B / Heutink, Peter / Sharma, Manu / Anonymous350918. ·Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands; Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA; Data Tecnica International, Glen Echo, MD, USA. · University California Irvine, Irvine, CA, USA. · Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. · Department of Internal Medicine, 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. · MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales, UK. · Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France. · Reta Lila Weston Institute, University College London, London, UK. · Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. · Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. Electronic address: manu.sharma@uni-tuebingen.de. ·Neurobiol Aging · Pubmed #28867149.

ABSTRACT: Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks.

25 Article GBA-Associated Parkinson's Disease: Progression in a Deep Brain Stimulation Cohort. 2017

Lythe, Vanessa / Athauda, Dilan / Foley, Jennifer / Mencacci, Niccolò E / Jahanshahi, Marjan / Cipolotti, Lisa / Hyam, Jonathan / Zrinzo, Ludvic / Hariz, Marwan / Hardy, John / Limousin, Patricia / Foltynie, Tom. ·Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK. · Department of Neuropsychology, National Hospital for Neurology and Neurosurgery, London, UK. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. ·J Parkinsons Dis · Pubmed #28777757.

ABSTRACT: BACKGROUND: Recent evidence suggests that glucosidase beta acid (GBA) mutations predispose Parkinson's disease (PD) patients to a greater burden of cognitive impairment and non-motor symptoms. This emerging knowledge has not yet been considered in patients who have undergone deep brain stimulation (DBS); a surgery that is generally contraindicated in those with cognitive deficits. OBJECTIVE: To explore the long-term phenotypic progression of GBA-associated PD, in a DBS cohort. METHODS: Thirty-four PD patients who had undergone DBS surgery between 2002 and 2011 were included in this study; 17 patients with GBA mutations were matched to 17 non-carriers. Clinical evaluation involved the administration of four assessments: The Mattis Dementia Rating Scale was used to assess cognitive function; non-motor symptoms were assessed using the Non-Motor Symptom Assessment Scale for PD; quality of life was measured using the Parkinson's Disease Questionnaire; and motor symptoms were evaluated using part III of the Movement Disorders Society Unified Parkinson's Disease Rating Scale, in on-medication/on-stimulation conditions. Levodopa equivalent doses (LED) and DBS settings were compared with clinical outcomes. RESULTS: At a mean follow-up of 7.5 years after DBS, cognitive impairment was more prevalent (70% vs 19%) and more severe in GBA mutation carriers compared to non-carriers (60% vs 6% were severely impaired). Non-motor symptoms were also more severe and quality of life more impaired in GBA-associated PD. Motor symptoms, LED, and stimulation settings were not significantly different between groups at follow-up. CONCLUSIONS: GBA status appears to be an important predictor for non-motor symptom disease progression, after deep brain stimulation surgery.

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