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TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis

journal contribution
posted on 2023-06-08, 13:42 authored by Jemeen Sreedharan, Nigel LeighNigel Leigh, Ian P Blair, Vineeta B Tripathi, Xun Hu, Boris Rogelj, Steven Ackerley, Jennifer C Durnall, Kelly L Williams, Emanuele Buratti, Francisco Baralle, Jacqueline de Belleroche, J Douglas Mitchell, others
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.

History

Publication status

  • Published

Journal

Science

ISSN

1095-9203

Publisher

American Association for the Advancement of Science

Issue

5870

Volume

319

Page range

1668-72

Department affiliated with

  • Clinical and Experimental Medicine Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-11-14

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