TDP-43 depletion: mechanism of neuronal cell death in ALS

Trans activation response DNA/RNA-binding protein 43 kDa (TDP-43) regulates RNA splicing and stability. TDP-43 is a component of ubiquitin-positive inclusion bodies of motor neurons from patients with amyotrophic lateral sclerosis, suggesting a role in disease pathogenesis. Toxic intracellular TDP-43 aggregation may cause neuronal cell death. The loss of TDP-43 in animal models causes lethality in early development. Furthermore, TDP-43 knockdown in adult animals and cells increases aberrant splicing. Uridine-rich small nuclear RNA (U snRNA) regulation is disrupted in cultured neuroblastoma cells with TDP-43 knockdown and in motor neurons in amyotrophic lateral sclerosis. Aberrant mRNA splicing and U snRNA expression are likely key processes in neuronal cell death. We review the research history and future perspectives of aberrant splicing by TDP-43 loss.