Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of both upper and lower motor neurons. Most ALS cases are sporadic, but approximately 5–10% of patients have a familial background. To date, more than 30 familial ALS-causative genes have been identified (Maurel et al., 2018). The clinical manifestation and disease progression of sporadic ALS and familial ALS are similar and often clinically and pathologically indistinguishable, suggesting that they share a common pathophysiology in motor neuronal degeneration. One of the pathological hallmarks of ALS is the mislocalization of a multifunctional nuclear protein, TAR-DNA binding protein 43 (TDP-43). TDP-43 was identified as a primary component of ubiquitin-positive cytosolic inclusion bodies seen in remnant motor neurons in both sporadic and familial ALS (Neumann et al., 2006), and was later recognized as an autosomal dominant familial ALS-causative gene (ALS10) (Sreedharan et al., 2008). Since the cytosolic inclusion of TDP-43 is seen in almost all cases of ALS, regardless of the TDP-43 genotype, TDP-43 is thought to be a central hub molecule, linking both familial and sporadic ALS. Therefore, elucidation of the molecular mechanisms underlying TDP-43-related neurotoxicity would contribute to understanding the pathophysiology of this merciless disease.