Showing papers by "Jan O. Aasly published in 2020"
Mayo Clinic1, University College London2, UCL Institute of Neurology3, Harvard University4, Lund University5, University of Coimbra6, University of Memphis7, Brown University8, University of Michigan9, Niigata University10, Norwegian University of Science and Technology11, Oregon Health & Science University12, University of Alabama at Birmingham13
TL;DR: An immunoassay is developed that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias, and a single-nucleotide polymorphism is identified that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXn3.
Abstract: Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.
29 citations
Indiana University1, Google2, Columbia University3, University of Miami4, University of Kiel5, University of Tübingen6, Icahn School of Medicine at Mount Sinai7, University of Paris8, German Center for Neurodegenerative Diseases9, National Institutes of Health10, University of Pennsylvania11, McKnight Brain Institute12, University of Florida13, University of British Columbia14, Toronto Western Hospital15, Stanford University16, Mater Misericordiae University Hospital17, Albany Medical College18, Boston University19, University of Alabama at Birmingham20, University of Toronto21, University of South Florida22, University College Dublin23, University of Washington24, University of California, San Francisco25, University of Barcelona26, University of Reading27, Tel Aviv Sourasky Medical Center28, Michael J. Fox Foundation29
TL;DR: The first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers suggests that variants within or near CORO1C may modify the penetrance of L RRK2 mutations.
Abstract: Objective The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson’s disease. Methods We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson’s disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson’s disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value=2.5E-08, beta=1.27, SE=0.23, risk allele: C) met genome-wide significance for the penetrance model. A region on chromosome 3, within a previously reported linkage peak for Parkinson’s disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value=1.1E-07; age-at-onset top variant: P-value=9.3E-07). A polygenic risk score derived from publicly available Parkinson’s disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson’s disease associated variants collectively increase the penetrance of LRRK2 mutations.
5 citations