ALS or FTD-linked CHMP2B mutants have aberrant autoregulation which results in the prolonged engagement of the ESCRT-III complex with the MVB membrane causing defects in endosome/MVB-lysosome fusion events and general endolysosomal function that coincide with autophagosome accumulation and a reduction in the autophagic flux [363,365,367,370-372]. The gene discussed is CHMP2B; the disease is amyotrophic lateral sclerosis.