Here, we review the neuropathological and genetic evidence of oligodendrocyte impairment in TDP-43/FUS-proteinopathies, summarize current insights into the roles of TDP-43 and FUS in oligodendrocytes, and discuss the potential impact of altered oligodendroglial functions in ALS/FTLD pathogenesis. Here, TARDBP is linked to proteostasis deficiencies.