ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization
Author:
Tazelaar Gijs H P1, Boeynaems Steven234, De Decker Mathias23, van Vugt Joke J F A1, Kool Lindy1, Goedee H Stephan1, McLaughlin Russell L5, Sproviero William6, Iacoangeli Alfredo7, Moisse Matthieu23, Jacquemyn Maarten8, Daelemans Dirk8, Dekker Annelot M1, van der Spek Rick A1, Westeneng Henk-Jan1, Kenna Kevin P1, Assialioui Abdelilah9, Da Silva Nica6, Akçimen Fulya, Al Khleifat Ahmad, Al-Chalabi Ammar, Andersen Peter, Basak A Nazli, Bauer Denis C, Blair Ian, Brands William J, Byrne Ross P, Calvo Andrea, Gonzalez Yolanda Campos, Chio Adriano, Cooper-Knock Jonothan, Corcia Philippe, Couratier Philippe, de Carvalho Mamede, Dekker Annelot M, Drory Vivian E, Eitan Chen, Redondo Alberto Garcia, Gellera Cinzia, Glass Jonathan D, Gotkine Marc, Hardiman Orla, Hornstein Eran, Iacoangeli Alfredo, Kenna Kevin P, Kenna Brandon, Kiernan Matthew C, Kocoglu Cemile, Kooyman Maarten, Landers John E, Alonso Victoria López, McLaughlin Russell L, Middelkoop Bas, Mill Jonathan, Mitne-Neto Miguel, Moisse Matthieu, Mora Pardina Jesus S, Morrison Karen E, Pinto Susana, Gromicho Marta, Panadés Monica Povedano, Pulit Sara L, Ratti Antonia, Robberecht Wim, Schellevis Raymond D, Shatunov Aleksey, Shaw Christopher E, Shaw Pamela J, Silani Vincenzo, Sproviero William, Staiger Christine, Tazelaar Gijs H P, Ticozzi Nicola, Tunca Ceren, Twine Nathalie A, van Damme Philip, van den Berg Leonard H, van der Spek Rick A, van Doormaal Perry T C, van Eijk Kristel R, van Es Michael A, van Rheenen Wouter, van Vugt Joke J F A, Veldink Jan H, Visscher Peter M, Vourc’h Patrick, Weber Markus, Williams Kelly L, Wray Naomi, Yang Jian, Zatz Mayana, Zhang Katharine, Povedano Mónica9, Pardina Jesus S Mora10, Hardiman Orla1112, Salachas François1314, Millecamps Stéphanie14, Vourc’h Patrick15, Corcia Philippe16ORCID, Couratier Philippe17, Morrison Karen E18, Shaw Pamela J19, Shaw Christopher E620, Pasterkamp R Jeroen21, Landers John E22, Van Den Bosch Ludo23, Robberecht Wim2323, Al-Chalabi Ammar620, van den Berg Leonard H1, Van Damme Philip2323ORCID, Veldink Jan H1, van Es Michael A1ORCID,
Affiliation:
1. Department of Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, University of Utrecht, 3508 GA, Utrecht, The Netherlands 2. Division of Experimental Neurology, Department of Neurosciences, KU Leuven—University of Leuven, Leuven 3000, Belgium 3. Laboratory of Neurobiology, VIB, Center for Brain & Disease Research, Leuven 3000, Belgium 4. Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305-5120, USA 5. Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin D02 PN40, Republic of Ireland 6. Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, King’s College London, London SE5 9NU, UK 7. Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 9NU, UK 8. KU Leuven Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium 9. Servei de Neurologia, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona 08908, Spain 10. ALS Unit, Hospital San Rafael, Madrid 28016, Spain 11. Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin D02 PN40, Republic of Ireland 12. Department of Neurology, Beaumont Hospital, Dublin D02 PN40, Republic of Ireland 13. Centre de compétence SLA-Département de Neurologie, Hôpital Pitié-Salpêtrière, Paris 75651, France 14. Institut du Cerveau et de la Moelle Epinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, Paris 75651, France 15. INSERM U930, Université François Rabelais, Tours 92120, France 16. Centre de compétence SLA-fédération Tours-Limoges, Tours 92120, France 17. Centre de compétence SLA-fédération Tours-Limoges, Limoges 87100, France 18. Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK 19. Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK 20. Department of Neurology, King’s College Hospital, London SE5 9RS, UK 21. Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Utrecht University, 3508 GA, Utrecht, The Netherlands 22. Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA 23. Department of Neurology, University Hospitals Leuven, Leuven 3000, Belgium
Abstract
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 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.
Funder
ALS Foundation Netherlands, the Belgian ALS Liga and National Lottery, Agency for Innovation by Science and Technology (IWT), and the MND Association
Publisher
Oxford University Press (OUP)
Subject
General Earth and Planetary Sciences,General Environmental Science
Cited by
38 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献
|
|