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

Gijs H P Tazelaar; Steven Boeynaems; Mathias De Decker; Joke J F A van Vugt; Lindy Kool; H Stephan Goedee; Russell L McLaughlin; William Sproviero; Alfredo Iacoangeli; Matthieu Moisse; Maarten Jacquemyn; Dirk Daelemans; Annelot M Dekker; Rick A van der Spek; Henk-Jan Westeneng; Kevin P Kenna; Abdelilah Assialioui; Nica Da Silva; Mónica Povedano; Jesus S Mora Pardina; Orla Hardiman; François Salachas; Stéphanie Millecamps; Patrick Vourc'h; Philippe Corcia; Philippe Couratier; Karen E Morrison; Pamela J Shaw; Christopher E Shaw; R Jeroen Pasterkamp; John E Landers; Ludo Van Den Bosch; Wim Robberecht; Ammar Al-Chalabi; Leonard H van den Berg; Philip Van Damme; Jan H Veldink; Michael A van Es

doi:10.1093/braincomms/fcaa064

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

Gijs H P Tazelaar, Steven Boeynaems, Mathias De Decker, Joke J F A van Vugt, Lindy Kool, H Stephan Goedee, Russell L McLaughlin, William Sproviero, Alfredo Iacoangeli, Matthieu Moisse, Maarten Jacquemyn, Dirk Daelemans, Annelot M Dekker, Rick A van der Spek, Henk-Jan Westeneng, Kevin P Kenna, Abdelilah Assialioui, Nica Da Silva, Mónica Povedano, Jesus S Mora PardinaOrla Hardiman, François Salachas, Stéphanie Millecamps, Patrick Vourc'h, Philippe Corcia, Philippe Couratier, Karen E Morrison, Pamela J Shaw, Christopher E Shaw, R Jeroen Pasterkamp, John E Landers, Ludo Van Den Bosch, Wim Robberecht, Ammar Al-Chalabi, Leonard H van den Berg, Philip Van Damme, Jan H Veldink, Michael A van Es

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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
Journal	Brain communications
Volume	2
Issue number	2
Early online date	19 May 2020
DOIs	https://doi.org/10.1093/braincomms/fcaa064
Publication status	Early online date - 19 May 2020
Externally published	Yes

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ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization
Copyright 2020 the authors. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an open access Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction for non-commercial purposes, provided the author and source are cited.
Final published version, 1.03 MBLicence: CC BY-NC

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Tazelaar, G. H. P., Boeynaems, S., De Decker, M., van Vugt, J. J. F. A., Kool, L., Goedee, H. S., McLaughlin, R. L., Sproviero, W., Iacoangeli, A., Moisse, M., Jacquemyn, M., Daelemans, D., Dekker, A. M., van der Spek, R. A., Westeneng, H.-J., Kenna, K. P., Assialioui, A., Da Silva, N., Povedano, M., ... van Es, M. A. (2020). ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization. Brain communications, 2(2). Advance online publication. https://doi.org/10.1093/braincomms/fcaa064

@article{cb6737466b0844e59980181175461565,

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.",

author = "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 Henk-Jan Westeneng 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 = "{\textcopyright} The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.",

year = "2020",

month = may,

day = "19",

doi = "10.1093/braincomms/fcaa064",

language = "English",

volume = "2",

journal = "Brain communications",

issn = "2632-1297",

publisher = "Oxford University Press",

number = "2",

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Tazelaar, GHP, Boeynaems, S, De Decker, M, van Vugt, JJFA, Kool, L, Goedee, HS, McLaughlin, RL, Sproviero, W, Iacoangeli, A, Moisse, M, Jacquemyn, M, Daelemans, D, Dekker, AM, van der Spek, RA, Westeneng, H-J, Kenna, KP, Assialioui, A, Da Silva, N, Povedano, M, Pardina, JSM, Hardiman, O, Salachas, F, Millecamps, S, Vourc'h, P, Corcia, P, Couratier, P, Morrison, KE, Shaw, PJ, Shaw, CE, Pasterkamp, RJ, Landers, JE, Van Den Bosch, L, Robberecht, W, Al-Chalabi, A, van den Berg, LH, Van Damme, P, Veldink, JH & van Es, MA 2020, 'ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization', Brain communications, vol. 2, no. 2. https://doi.org/10.1093/braincomms/fcaa064

TY - JOUR

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

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

PY - 2020/5/19

Y1 - 2020/5/19

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.

U2 - 10.1093/braincomms/fcaa064

DO - 10.1093/braincomms/fcaa064

M3 - Article

C2 - 32954321

SN - 2632-1297

VL - 2

JO - Brain communications

JF - Brain communications

IS - 2

ER -

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

Abstract

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