ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization
Project MinE ALS Sequencing Consortium
(2020) Brain communications, volume 2, issue 2, pp. 1 - 13
(Article)
Abstract
Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification
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of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P = 3.33 × 10-7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.
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Keywords: amyotrophic lateral sclerosis, DNA repeat expansion, genetic association study, trinucleotide repeat expansions, Psychiatry and Mental health, Biological Psychiatry, Cellular and Molecular Neuroscience, Neurology, Journal Article
ISSN: 2632-1297
Publisher: Oxford University Press
Note: Funding Information: This study was supported by the ALS Foundation Netherlands, the Belgian ALS Liga and National Lottery, Agency for Innovation by Science and Technology (IWT), and the MND Association (UK) (Project MinE, www.project mine.com). Research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007-2013). This study was supported by ZonMW under the frame of E-Rare-2, the ERA Net for Research on Rare Diseases (PYRAMID). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no 772376-EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health-Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project (STRENGTH, BRAIN-MEND, SOPHIA, ALSCarE). The project is supported through the following funding organizations under the aegis of JPND: UK, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1); Ireland, Health Research Board; Netherlands, ZonMw; Belgium, FWO-Vlaanderen. Samples used in this research were in part obtained from the UK National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust. This project was supported by the MND Association of England, Wales and Northern Ireland and the Netherlands Organisation for Health Research and Development (Vici scheme to L.H.v.d.B. and Veni scheme to M.A.v.E.). NDAL cordially thanks Suna and Inan Kirac Foundation for their generous support. Funding was provided by US National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) (R01NS073873, J.E.L.) and the American ALS Association (J.E.L.). S.B. holds an EMBO long-term fellowship. M.A.v.E. is supported by the Thierry Latran Foundation, the Dutch ALS Foundation and the Rudolf Magnus Brain Center Talent Fellowship. A.A.-C. receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit and Biomedical Research Centre in Mental Health at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. O.H. is funded by the Health Research Board Clinician Scientist Programme and Science Foundation Ireland. R.L.M. is supported by the Thierry Latran Foundation (ALSIBD) and the ALS Association (2284). P.V.D. holds a senior clinical investigatorship from FWO-Vlaanderen and is supported by the ALS Liga België, Een hart voor ALS and the Laevers fund for ALS research. S.M. is supported by the Association française contre les myopathies (AFM) and the Association pour la Recherche sur la Sclérose latérale amyotrophique et autres maladies du motoneurone (ARSla). Publisher Copyright: © 2020 The Author(s).
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