The study investigates the role of TDP-43 mutations in amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The researchers identified three missense mutations in exon 6 of the TARDBP gene in both familial and sporadic ALS cases: M337V, Q331K, and G294A. The M337V mutation segregated with disease within a kindred and was linked to chromosome 1p36, confirming its pathogenicity. Mutant TDP-43 fragments more readily than wild-type and causes neural apoptosis and developmental delay in chick embryos. These findings suggest a pathophysiological link between TDP-43 and ALS, highlighting the importance of understanding the biochemical processes responsible for TDP-43's increased fragmentation and toxicity to neural tissues.The study investigates the role of TDP-43 mutations in amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The researchers identified three missense mutations in exon 6 of the TARDBP gene in both familial and sporadic ALS cases: M337V, Q331K, and G294A. The M337V mutation segregated with disease within a kindred and was linked to chromosome 1p36, confirming its pathogenicity. Mutant TDP-43 fragments more readily than wild-type and causes neural apoptosis and developmental delay in chick embryos. These findings suggest a pathophysiological link between TDP-43 and ALS, highlighting the importance of understanding the biochemical processes responsible for TDP-43's increased fragmentation and toxicity to neural tissues.