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.
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http://dx.doi.org/10.1186/s13059-017-1147-9 | DOI Listing |
J Med Internet Res
January 2025
Knight Foundation of Computing & Information Sciences, Florida International University, Miami, FL, United States.
Background: Digital biomarkers are increasingly used in clinical decision support for various health conditions. Speech features as digital biomarkers can offer insights into underlying physiological processes due to the complexity of speech production. This process involves respiration, phonation, articulation, and resonance, all of which rely on specific motor systems for the preparation and execution of speech.
View Article and Find Full Text PDFInt J Syst Evol Microbiol
January 2025
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Small, obligately anaerobic strains 13CB8C, 13CB11C, 13CB18C and 13GAM1G were isolated from a faecal sample in a patient with Parkinson's disease with a history of duodenal resection. After conducting a comprehensive polyphasic taxonomic analysis including genomic analysis, we propose the establishment of one new genus and four new species. The novel bacteria are sp.
View Article and Find Full Text PDFNeurology
February 2025
Health Services Research Program, Department of Neurology, University of Michigan, Ann Arbor; and.
Background And Objectives: Timely access to specialist care is crucial in expeditious diagnosis and treatment. Our study aimed to assess the time patients wait from being referred by a physician to seeing a neurologist using Medicare data. Specifically, we evaluated differences in access related to sex, race/ethnicity, geography, and availability of neurologists.
View Article and Find Full Text PDFMov Disord
January 2025
Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Background: Wider step width and lower step-to-step variability are linked to improved gait stability and reduced fall risk. It is unclear if patients with spinocerebellar ataxia (SCA) can learn to adjust these aspects of gait to reduce fall risk.
Objectives: The aims were to examine the possibility of using wearable step width haptic biofeedback to enhance gait stability and reduce fall risk in individuals with SCA.
Aging Ment Health
January 2025
Institute of Applied Psychology, University of the Punjab, Lahore, Pakistan.
Objectives: Disease-related stigma is associated with poor mental health and wellbeing in people with Parkinson's disease. Urdu language tools for measuring stigma are not yet available. The aim of this study was therefore to develop and validate an Urdu version of the Stigma Scale for Chronic Illness-8 (SSCI-8).
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