TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis

Sreedharan, Jemeen, Leigh, P Nigel, Blair, Ian P, Tripathi, Vineeta B, Hu, Xun, Rogelj, Boris, Ackerley, Steven, Durnall, Jennifer C, Williams, Kelly L, Buratti, Emanuele, Baralle, Francisco, de Belleroche, Jacqueline, Mitchell, J Douglas and others, (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science, 319 (5870). pp. 1668-72. ISSN 1095-9203

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Abstract

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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Brighton and Sussex Medical School > Neuroscience
Subjects: R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry > RC0346 Neurology. Diseases of the nervous system Including speech disorders
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Depositing User: Patricia Butler
Date Deposited: 14 Nov 2012 17:43
Last Modified: 10 Jan 2020 09:29
URI: http://sro.sussex.ac.uk/id/eprint/42522
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