TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

TLDR

Amyotrophic lateral sclerosis is a fatal motor neuron disorder marked by ubiquitinated TDP‑43 inclusions, yet the protein’s function and its mechanistic role in neurodegeneration remain unclear. The study uncovered pathogenic TARDBP mutations in a conserved region that segregate with ALS, fragment more readily than wild type, induce neural apoptosis and developmental delay, and provide evidence for a pathophysiological link between TDP‑43 and ALS.

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.