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Updated: Oct 18, 2025
Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
Published on: November 6, 2017
IP3R-driven increases in mitochondrial Ca2+ promote neuronal death in NPC disease
Scott A Tiscione1, Maria Casas1, Jonathan D Horvath1
1Department of Physiology and Membrane Biology, University of California, Davis, CA 95616.
Abstract:
Ca2+ 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 Ca2+ handling proteins; thus, elucidating molecular pathways that shape Ca2+ 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 IP3R type 1 (IP3R1) in endoplasmic reticulum membranes. These alterations detrimentally increase Gq-protein coupled receptor-stimulated Ca2+ release and spontaneous IP3R1 Ca2+ activity, leading to mitochondrial Ca2+ cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IP3R1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca2+ phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IP3R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease.
Insights
Niemann-Pick Type C1 (NPC1) mutations disrupt neuronal calcium (Ca2+) signaling by altering IP3R1 distribution and activity, leading to cell death. This pathway involves Presenilin 1 (PS1) and highlights NPC1's role in nanostructural disease.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Calcium (Ca2+) is a critical second messenger in neurons, regulating diverse signaling pathways.
- Dysregulation of Ca2+ homeostasis is implicated in numerous neuropathologies.
- Niemann-Pick Type C1 (NPC1) is a lysosomal cholesterol transporter whose dysfunction is linked to neurodegeneration.
Purpose of the Study:
- To investigate the molecular mechanisms by which NPC1 mutations affect neuronal Ca2+ signaling.
- To identify the downstream effectors and pathways involved in NPC1-associated neurotoxicity.
- To elucidate the role of IP3R1 and Presenilin 1 (PS1) in NPC1 disease.
Main Methods:
- Utilized loss-of-function and knockout models of NPC1.
- Analyzed alterations in IP3R1 expression and nanoscale distribution in endoplasmic reticulum membranes.
- Assessed Gq-protein coupled receptor-stimulated Ca2+ release and spontaneous IP3R1 Ca2+ activity.
- Investigated the role of SREBP and PS1 in NPC1-related Ca2+ dysregulation.
Main Results:
- NPC1 loss-of-function or mutations alter IP3R1 expression and nanoscale distribution.
- These alterations lead to increased Gq-protein coupled receptor-stimulated Ca2+ release and spontaneous IP3R1 activity.
- SREBP-dependent upregulation of PS1 mediates the functional and expressional changes in IP3R1.
- PS1 mutants recapitulate, while PS1 knockout abrogates, the observed Ca2+ phenotypes.
Conclusions:
- A signaling axis links NPC1 to detrimental IP3R1 redistribution and activity, precipitating cell death in NPC1 disease.
- NPC1 dysfunction initiates a cascade involving PS1, leading to aberrant Ca2+ signaling and mitochondrial cytotoxicity.
- NPC1 is identified as a nanostructural disease, emphasizing the importance of molecular organization in neuronal function and disease pathogenesis.
