期刊
JOURNAL OF CELL BIOLOGY
卷 218, 期 12, 页码 4141-4156出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201903018
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资金
- Pharmacology National Institutes of Health T32 training award [T32GM099608]
- National Institutes of Health [R01 GM127513, R01 HL142282, R01 HL06773, R01 HL085686, R01 AG063796]
- American Heart Association [15SDG25560035]
- Ara Parseghian Medical Research Foundation award
- University of California funds
Niemann-Pick type Cl (NPC1) protein is essential for the transport of externally derived cholesterol from lysosomes to other organelles. Deficiency of NPC1 underlies the progressive NPC1 neurodegenerative disorder. Currently, there are no curative therapies for this fatal disease. Given the Ca2+ hypothesis of neurodegeneration, which posits that altered Ca2+ dynamics contribute to neuropathology, we tested if disease mutations in NPC1 alter Ca2+ signaling and neuronal plasticity. We determine that NPC1 inhibition or disease mutations potentiate store-operated Ca2+ entry (SOCE) due to a presenilin 1 (PSEN1)-dependent reduction in ER Ca2+ levels alongside elevated expression of the molecular SOCE components ORAI1 and STIM1. Associated with this dysfunctional Ca2+ signaling is destabilization of neuronal dendritic spines. Knockdown of PSEN1 or inhibition of the SREBP pathway restores Ca2+ homeostasis, corrects differential protein expression, reduces cholesterol accumulation, and rescues spine density. These findings highlight lysosomes as a crucial signaling platform responsible for tuning ER Ca2+ signaling, SOCE, and synaptic architecture in health and disease.
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