TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

作者：Jemeen Sreedharan, Ian P. Blair, Vineeta B. Tripathi, Xun Hu, Caroline Vance, Boris Rogelj, Steven Ackerley, Jennifer C. Durnall, Kelly L. Williams, Emanuele Buratti, Francisco E. Baralle, Jacqueline de Belleroche, John D. Mitchell, P. Nigel Leigh, Ammar Al‐Chalabi, Christopher C.J. Miller, Garth A. Nicholson, Christopher E. Shaw · 发表于：Science · 年份：2008 · DOI：10.1126/science.1154584 · 被引用次数：2659 · 研究领域：Amyotrophic Lateral Sclerosis Research、Neurogenetic and Muscular Disorders Research、Prion Diseases and Protein Misfolding

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.