Open AccessIP 3 R-driven increases in mitochondrial Ca 2+ promote neuronal death in NPC disease
Author(s) -
Scott A. Tiscione,
Maria Casas,
Jonathan D. Horvath,
Vincent Lam,
Keiko Hino,
Daniel S. Ory,
Luis Fernando Santana,
Sergi Simó,
Rose E. Dixon,
Eamonn J. Dickson
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2110629118
Subject(s) - endoplasmic reticulum , microbiology and biotechnology , npc1 , golgi apparatus , biology , intracellular , calcium signaling , neurodegeneration , signal transduction , hek 293 cells , mitochondrion , receptor , biochemistry , endosome , disease , medicine
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 IP3 R type 1 that precipitates neuron death. Targeting IP3 R1 or upstream elements of this signaling cascade rescues neuronal death and provides potential therapeutic targets to address IP3 R dysfunction, a feature of NPC1 disease and other neurodegenerative disorders.