TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis by Sreedharan Jemeen, Blair Ian P, Tripathi Vineeta B, Hu Xun, Vance Caroline, Rogelj Boris, Ackerley Steven, Durnall Jennifer C, Williams Kelly L, Buratti Emanuele, Baralle Francisco, de Belleroche Jacqueline, Mitchell J Douglas, Leigh P Nigel, Al-Chalabi Ammar, Miller Christopher C, Nicholson Garth, Shaw Christopher E in Science (New York, N.Y.) (2008).

[PMID: 18309045] PubMed


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.

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