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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)\u2013dependent 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.<\/jats:p>","DOI":"10.1083\/jcb.201903018","type":"journal-article","created":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T18:49:13Z","timestamp":1570733353000},"page":"4141-4156","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":46,"title":["Disease-associated mutations in Niemann-Pick type C1 alter ER calcium signaling and neuronal plasticity"],"prefix":"10.1083","volume":"218","author":[{"given":"Scott A.","family":"Tiscione","sequence":"first","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0964-385X","authenticated-orcid":true,"given":"Oscar","family":"Vivas","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth S.","family":"Ginsburg","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Davis, Davis, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2237-9483","authenticated-orcid":true,"given":"Donald M.","family":"Bers","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Davis, Davis, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel S.","family":"Ory","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4297-8029","authenticated-orcid":true,"given":"Luis F.","family":"Santana","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0655-690X","authenticated-orcid":true,"given":"Rose E.","family":"Dixon","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8619-7630","authenticated-orcid":true,"given":"Eamonn J.","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2019,10,10]]},"reference":[{"key":"2023072401461711700_bib1","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.jalz.2016.12.006","article-title":"Calcium Hypothesis of Alzheimer\u2019s disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis","volume":"13","author":"Alzheimer\u2019s Association Calcium Hypothesis Workgroup","year":"2017","journal-title":"Alzheimers Dement."},{"key":"2023072401461711700_bib2","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/s00424-009-0736-1","article-title":"Calcium hypothesis of Alzheimer\u2019s disease","volume":"459","author":"Berridge","year":"2010","journal-title":"Pflugers Arch."},{"key":"2023072401461711700_bib3","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/1750-1326-8-23","article-title":"The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration","volume":"8","author":"Bezprozvanny","year":"2013","journal-title":"Mol. 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