IP(3)R-driven increases in mitochondrial Ca(2+) promote neuronal death in NPC disease

Ca(2+) 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(2+) handling proteins; thus, elucidating molecular pathways that shape Ca(2+) 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 IP(3)R type 1 (IP(3)R1) in endoplasmic reticulum membranes. These alterations detrimentally increase G(q)-protein coupled receptor–stimulated Ca(2+) release and spontaneous IP(3)R1 Ca(2+) activity, leading to mitochondrial Ca(2+) cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IP(3)R1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca(2+) phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IP(3)R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease.