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Loss of autophagy in actively respiring cells has also been shown to trigger metabolic collapse mediated by the depletion of nicotinamide adenine dinucleotide (NAD) pools, resulting in cell death. Here we found that the deficit in the autophagy-NAD axis underpins the loss of viability in cell models of a neurodegenerative lysosomal storage disorder, Niemann-Pick type C1 (NPC1) disease. Defective autophagic flux in NPC1 cells resulted in mitochondrial dysfunction due to impairment of mitophagy, leading to the depletion of both the reduced and oxidised forms of NAD as identified via metabolic profiling. Consequently, exhaustion of the NAD pools triggered mitochondrial depolarisation and apoptotic cell death. Our chemical screening identified two FDA-approved drugs, celecoxib and memantine, as autophagy activators which effectively restored autophagic flux, NAD levels, and cell viability of NPC1 cells. Of biomedical relevance, either pharmacological rescue of the autophagy deficiency or NAD precursor supplementation restored NAD levels and improved the viability of NPC1 patient fibroblasts and induced pluripotent stem cell (iPSC)-derived cortical neurons. Together, our findings identify the autophagy-NAD axis as a mechanism of cell death and a target for therapeutic interventions in NPC1 disease, with a potential relevance to other neurodegenerative disorders.<\/jats:p>","DOI":"10.1038\/s41419-024-06770-y","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T11:10:44Z","timestamp":1717153844000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3958-5232","authenticated-orcid":false,"given":"Tetsushi","family":"Kataura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4482-088X","authenticated-orcid":false,"given":"Lucia","family":"Sedlackova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congxin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1164-367X","authenticated-orcid":false,"given":"Gamze","family":"Kocak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niall","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Banks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faisal","family":"Hayat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Trushin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-2860","authenticated-orcid":false,"given":"Eugenia","family":"Trushina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5551-9091","authenticated-orcid":false,"given":"Oliver D. 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S. Sarkar is a scientific consultant for Ayin Tech LLC. V.I.K. is a Scientific Advisor for Longaevus Technologies.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study was performed in accordance with the Declaration of Helsinki. The control and NPC1 patient-derived fibroblasts were obtained from Coriell Cell Repositories and therefore exempt from institutional committee approval. The control and NPC1 patient-derived iPSCs were originally generated in the lab of Rudolf Jaenisch at the Whitehead Institute for Biomedical Research using protocols approved by the relevant Institutional Review Board (Massachusetts Institute of Technology) and the Embryonic Stem Cell Research Oversight Committees (Whitehead Institute). 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