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

Significance

NPC1 is a ubiquitously expressed lysosomal cholesterol transporter whose loss of function results in neurodegenerative NPC1 disease. Here, we report that loss-of-function, knockout, or mutation-causing NPC1 initiates a damaging signaling cascade that alters the expression and nanoscale distribution of IP ₃R type 1 that precipitates neuron death. Targeting IP ₃R1 or upstream elements of this signaling cascade rescues neuronal death and provides potential therapeutic targets to address IP ₃R dysfunction, a feature of NPC1 disease and other neurodegenerative disorders.

Abstract

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 ₃R type 1 (IP ₃R1) in endoplasmic reticulum membranes. These alterations detrimentally increase G _q-protein coupled receptor–stimulated Ca ²⁺ release and spontaneous IP ₃R1 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 ₃R1. 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 ₃R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease.