“…Recent evidence suggests that dysfunction of the ESCRT machinery itself is associated with profound cytopathology, as brain-specific deletion of ESCRT components in mice leads to the accumulation of ubiquitylated proteins, impaired endosomal trafficking, and cell death (Oshima, Hasegawa et al, 2016, Watson, Bhattacharyya et al, 2015. Further, a truncating mutation in ESCRT-III protein CHMP2b causes familial frontotemporal dementia and amyotrophic lateral sclerosis, and at the cellular level induces endo-lysosomal pathway dysfunction and the accumulation of ubiquitylated proteins (Clayton, Mizielinska et al, 2015, Zhang, Schmid et al, 2017. Together with our findings, the above studies support the importance of the endo-lysosomal pathway, and specifically the ESCRT machinery, in the clearance of ubiquitylated proteins such as Tau.…”