ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization

Project MinE ALS Sequencing Consortium

doi:10.1093/braincomms/fcaa064

ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization

Project MinE ALS Sequencing Consortium

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

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.

Original language	English
Article number	fcaa064
Journal	Brain Communications
Volume	2
Issue number	2
DOIs	https://doi.org/10.1093/braincomms/fcaa064
Publication status	Published - 2020

Keywords

amyotrophic lateral sclerosis
DNA repeat expansion
genetic association study
trinucleotide repeat expansions

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/braincomms/fcaa064

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@article{e7c4c40562494e5ba126b4f304f2de96,

title = "ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization",

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. ",

keywords = "amyotrophic lateral sclerosis, DNA repeat expansion, genetic association study, trinucleotide repeat expansions",

author = "{Project MinE ALS Sequencing Consortium} and Tazelaar, {Gijs H.P.} and Steven Boeynaems and {De Decker}, Mathias and {Van Vugt}, {Joke J.F.A.} and Lindy Kool and Goedee, {H. Stephan} and Mclaughlin, {Russell L.} and William Sproviero and Alfredo Iacoangeli and Matthieu Moisse and Maarten Jacquemyn and Dirk Daelemans and Dekker, {Annelot M.} and {Van Der Spek}, {Rick A.} and Westeneng, {Henk Jan} and Kenna, {Kevin P.} and Abdelilah Assialioui and {Da Silva}, Nica and M{\'o}nica Povedano and Pardina, {Jesus S.Mora} and Orla Hardiman and Fran{\c c}ois Salachas and St{\'e}phanie Millecamps and Patrick Vourc'h and Philippe Corcia and Philippe Couratier and Morrison, {Karen E.} and Shaw, {Pamela J.} and Shaw, {Christopher E.} and Pasterkamp, {R. Jeroen} and Landers, {John E.} and {Van Den Bosch}, Ludo and Wim Robberecht and Ammar Al-Chalabi and {Van Den Berg}, {Leonard H.} and {Van Damme}, Philip and Veldink, {Jan H.} and {Van Es}, {Michael A.}",

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 Belgi{\"e}, Een hart voor ALS and the Laevers fund for ALS research. S.M. is supported by the Association fran{\c c}aise contre les myopathies (AFM) and the Association pour la Recherche sur la Scl{\'e}rose lat{\'e}rale amyotrophique et autres maladies du motoneurone (ARSla). Publisher Copyright: {\textcopyright} 2020 The Author(s).",

year = "2020",

doi = "10.1093/braincomms/fcaa064",

language = "English",

volume = "2",

journal = "Brain Communications",

issn = "2632-1297",

publisher = "Oxford University Press",

number = "2",

}

TY - JOUR

T1 - ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization

AU - Project MinE ALS Sequencing Consortium

AU - Tazelaar, Gijs H.P.

AU - Boeynaems, Steven

AU - De Decker, Mathias

AU - Van Vugt, Joke J.F.A.

AU - Kool, Lindy

AU - Goedee, H. Stephan

AU - Mclaughlin, Russell L.

AU - Sproviero, William

AU - Iacoangeli, Alfredo

AU - Moisse, Matthieu

AU - Jacquemyn, Maarten

AU - Daelemans, Dirk

AU - Dekker, Annelot M.

AU - Van Der Spek, Rick A.

AU - Westeneng, Henk Jan

AU - Kenna, Kevin P.

AU - Assialioui, Abdelilah

AU - Da Silva, Nica

AU - Povedano, Mónica

AU - Pardina, Jesus S.Mora

AU - Hardiman, Orla

AU - Salachas, François

AU - Millecamps, Stéphanie

AU - Vourc'h, Patrick

AU - Corcia, Philippe

AU - Couratier, Philippe

AU - Morrison, Karen E.

AU - Shaw, Pamela J.

AU - Shaw, Christopher E.

AU - Pasterkamp, R. Jeroen

AU - Landers, John E.

AU - Van Den Bosch, Ludo

AU - Robberecht, Wim

AU - Al-Chalabi, Ammar

AU - Van Den Berg, Leonard H.

AU - Van Damme, Philip

AU - Veldink, Jan H.

AU - Van Es, Michael A.

N1 - 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).

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - amyotrophic lateral sclerosis

KW - DNA repeat expansion

KW - genetic association study

KW - trinucleotide repeat expansions

UR - http://www.scopus.com/inward/record.url?scp=85094627397&partnerID=8YFLogxK

U2 - 10.1093/braincomms/fcaa064

DO - 10.1093/braincomms/fcaa064

M3 - Article

AN - SCOPUS:85094627397

SN - 2632-1297

VL - 2

JO - Brain Communications

JF - Brain Communications

IS - 2

M1 - fcaa064

ER -

ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization

Abstract

Keywords

UN SDGs

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