IPR-driven increases in mitochondrial Ca promote neuronal death in NPC disease.

Ca is the most ubiquitous second messenger in neurons whose spatial and temporal elevations are tightly controlled to initiate and orchestrate diverse intracellular signaling cascades. Numerous neuropathologies result from mutations or alterations in Ca handling proteins; thus, elucidating molecular pathways that shape Ca signaling is imperative. Here, we report that loss-of-function, knockout, or neurodegenerative disease-causing mutations in the lysosomal cholesterol transporter, Niemann-Pick Type C1 (NPC1), initiate a damaging signaling cascade that alters the expression and nanoscale distribution of IPR type 1 (IPR1) in endoplasmic reticulum membranes. These alterations detrimentally increase G-protein coupled receptor-stimulated Ca release and spontaneous IPR1 Ca activity, leading to mitochondrial Ca cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IPR1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IPR1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease.