Given the increasing evidence suggesting the existence of distinct TDP-43 strains that might propagate in a prion-like manner as a molecular basis for the distinct clinical and pathological TDP-43 proteinopathies (Kawakami et al., 2019; Neumann et al., 2021), it is tempting to speculate that ALS—TDP and FTLD types B and E might share common TDP-43 strains with a specific cellular tropism for oligodendrocytes. Here, TARDBP is linked to proteostasis deficiencies.