IP <sub>3</sub> R-driven increases in mitochondrial Ca <sup>2+</sup> promote neuronal death in NPC disease
Scott A. Tiscione, Maria Casas, Jonathan D. Horvath, Vincent Lam, Keiko Hino, Daniel Ory, Luis F. Santana, Sergi Simó, Rose E. Dixon, Eamonn J. Dickson
Abstract
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 3 R type 1 that precipitates neuron death. Targeting IP 3 R1 or upstream elements of this signaling cascade rescues neuronal death and provides potential therapeutic targets to address IP 3 R dysfunction, a feature of NPC1 disease and other neurodegenerative disorders.
Topics & Concepts
Endoplasmic reticulumCell biologyNPC1Golgi apparatusBiologyIntracellularCalcium signalingNeurodegenerationSignal transductionHEK 293 cellsMitochondrionReceptorBiochemistryEndosomeDiseaseMedicineInternal medicineLysosomal Storage Disorders ResearchCalcium signaling and nucleotide metabolismCellular transport and secretion