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

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.-.; Kenna, K.P.; Assialioui, A.; Silva, N.D.; Povedano, M.; Mora Pardina, J.S.; Hardiman, O.; Salachas, F.; Millecamps, S.; Vourc'H, P.; Corcia, P.; Couratier, P.; Morrison, K.E.; Shaw, P.J.; Shaw, C.E.; Pasterkamp, R.J.; Landers, J.E.; Van Den Bosch, L.; Robberecht, W.; Al-Chalabi, A.; Van Den Berg, L.H.; Van Damme, P.; Veldink, J.H.; Van Es, M.A.; Akcimen, F.; Al Khleifat, A.; Andersen, P.; Basak, A.N.; Bauer, D.C.; Blair, I.; Brands, W.J.; Byrne, R.P.; Calvo, A.; Gonzalez, Y.C.; Chio, A.; Cooper-Knock, J.; De Carvalho, M.; Drory, V.E.; Eitan, C.; Redondo, A.G.; Gellera, C.; Glass, J.D.; Gotkine, M.; Hornstein, E.; Kenna, B.; Kiernan, M.C.; Kocoglu, C.; Kooyman, M.; Alonso, V.L.; Middelkoop, B.; Mill, J.; Mitne-Neto, M.; Pinto, S.; Gromicho, M.; Panades, M.P.; Pulit, S.L.; Ratti, A.; Schellevis, R.D.; Shatunov, A.; Silani, V.; Staiger, C.; Ticozzi, N.; Tunca, C.; Twine, N.A.; Van Doormaal, P.T.C.; Van Eijk, K.R.; Van Rheenen, W.; Visscher, P.M.; Weber, M.; Williams, K.L.; Wray, N.; Yang, J.; Zatz, M.; Zhang, K.

doi:10.1093/braincomms/fcaa064

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.

ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization / G.H.P. Tazelaar, S. Boeynaems, M. De Decker, J.J.F.A. Van Vugt, L. Kool, H.S. Goedee, R.L. Mclaughlin, W. Sproviero, A. Iacoangeli, M. Moisse, M. Jacquemyn, D. Daelemans, A.M. Dekker, R.A. Van Der Spek, H.-. Westeneng, K.P. Kenna, A. Assialioui, N.D. Silva, M. Povedano, J.S. Mora Pardina, O. Hardiman, F. Salachas, S. Millecamps, P. Vourc'H, P. Corcia, P. Couratier, K.E. Morrison, P.J. Shaw, C.E. Shaw, R.J. Pasterkamp, J.E. Landers, L. Van Den Bosch, W. Robberecht, A. Al-Chalabi, L.H. Van Den Berg, P. Van Damme, J.H. Veldink, M.A. Van Es, F. Akcimen, A. Al Khleifat, P. Andersen, A.N. Basak, D.C. Bauer, I. Blair, W.J. Brands, R.P. Byrne, A. Calvo, Y.C. Gonzalez, A. Chio, J. Cooper-Knock, M. De Carvalho, V.E. Drory, C. Eitan, A.G. Redondo, C. Gellera, J.D. Glass, M. Gotkine, E. Hornstein, B. Kenna, M.C. Kiernan, C. Kocoglu, M. Kooyman, V.L. Alonso, B. Middelkoop, J. Mill, M. Mitne-Neto, S. Pinto, M. Gromicho, M.P. Panades, S.L. Pulit, A. Ratti, R.D. Schellevis, A. Shatunov, V. Silani, C. Staiger, N. Ticozzi, C. Tunca, N.A. Twine, P.T.C. Van Doormaal, K.R. Van Eijk, W. Van Rheenen, P.M. Visscher, M. Weber, K.L. Williams, N. Wray, J. Yang, M. Zatz, K. Zhang. - In: BRAIN COMMUNICATIONS. - ISSN 2632-1297. - 2:2(2020), pp. fcaa064.1-fcaa064.13. [10.1093/braincomms/fcaa064]

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

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.;Silva N. D.;Povedano M.;Mora Pardina J. S.;Hardiman O.;Salachas F.;Millecamps S.;Vourc'h P.;Corcia P.;Couratier P.;Morrison K. E.;Shaw P. J.;Shaw C. E.;Pasterkamp R. J.;Landers J. E.;Van Den Bosch L.;Robberecht W.;Al-Chalabi A.;van den Berg L. H.;Van Damme P.;Veldink J. H.;van Es M. A.;Akcimen F.;Al Khleifat A.;Andersen P.;Basak A. N.;Bauer D. C.;Blair I.;Brands W. J.;Byrne R. P.;Calvo A.;Gonzalez Y. C.;Chio A.;Cooper-Knock J.;de Carvalho M.;Drory V. E.;Eitan C.;Redondo A. G.;Gellera C.;Glass J. D.;Gotkine M.;Hornstein E.;Kenna B.;Kiernan M. C.;Kocoglu C.;Kooyman M.;Alonso V. L.;Middelkoop B.;Mill J.;Mitne-Neto M.;Pinto S.;Gromicho M.;Panades M. P.;Pulit S. L.;A. Ratti;Schellevis R. D.;Shatunov A.;V. Silani;Staiger C.;N. Ticozzi;Tunca C.;Twine N. A.;van Doormaal P. T. C.;van Eijk K. R.;van Rheenen W.;Visscher P. M.;Weber M.;Williams K. L.;Wray N.;Yang J.;Zatz M.;Zhang K.

2020

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.

Scheda breve

Scheda completa

Scheda completa (DC)

	Parole chiave
	
				amyotrophic lateral sclerosis; DNA repeat expansion; genetic association study; trinucleotide repeat expansions
			
	Settori scientifico-disciplinari dell'articolo (validi dal 09/05/2024)
	
				Settore MEDS-12/A - Neurologia
			
	Data di pubblicazione
	
				2020
			
	Rivista in ANCE
	
				BRAIN COMMUNICATIONS
			
	DOI
	
				https://dx.doi.org/10.1093/braincomms/fcaa064
			
	Tipologia
	
				Article (author)
			
	Appare nelle tipologie:
	
				01 - Articolo su periodico

File in questo prodotto:

File	Dimensione	Formato
fcaa064.pdf accesso aperto Tipologia: Publisher's version/PDF Licenza: Creative commons Dimensione 1.02 MB Formato Adobe PDF Visualizza/Apri	1.02 MB	Adobe PDF	Visualizza/Apri

Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1206178

Citazioni

ND

42

35

55

IRIS Institutional Research Information System - AIR Archivio Istituzionale della Ricerca