SigR1 is an ER chaperone protein involved in a variety of biological processes (reviewed in [323]) but expression of ALS/FTD-linked SIGMAR1 in cellular and mouse models negatively affects autophagy most likely due to a loss-of-function mechanism as SigR1 activation or overexpression can rescue these defects [324,325].Recent studies revealed that either expression of ALSD/FTD SigR1 mutants or ablation of endogenous SigR1 caused impaired endosomal trafficking and autophagic flux defects mediated by impairments in the autophagosome-lysosome fusion process [326-328]. Here, SIGMAR1 is linked to frontotemporal dementia.