Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models

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  • dc.contributor.author Kataura, Tetsushi
  • dc.contributor.author Sedlackova, Lucia
  • dc.contributor.author Sun, Congxin
  • dc.contributor.author Kocak, Gamze
  • dc.contributor.author Wilson, Niall
  • dc.contributor.author Banks, Peter
  • dc.contributor.author Hayat, Faisal
  • dc.contributor.author Trushin, Sergey
  • dc.contributor.author Trushina, Eugenia
  • dc.contributor.author Maddocks, Oliver D. K.
  • dc.contributor.author Oblong, John E.
  • dc.contributor.author Miwa, Satomi
  • dc.contributor.author Imoto, Masaya
  • dc.contributor.author Saiki, Shinki
  • dc.contributor.author Erskine, Daniel
  • dc.contributor.author Migaud, Marie E.
  • dc.contributor.author Sarkar, Sovan
  • dc.contributor.author Korolchuk, Viktor I.
  • dc.date.accessioned 2024-09-12T06:59:21Z
  • dc.date.available 2024-09-12T06:59:21Z
  • dc.date.issued 2024
  • dc.description.abstract Impairment of autophagy leads to an accumulation of misfolded proteins and damaged organelles and has been implicated in plethora of human diseases. 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.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Kataura T, Sedlackova L, Sun C, Kocak G, Wilson N, Banks P, et al. Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models. Cell Death Dis. 2024 May 31;15(5):382. DOI: 10.1038/s41419-024-06770-y
  • dc.identifier.doi http://dx.doi.org/10.1038/s41419-024-06770-y
  • dc.identifier.issn 2041-4889
  • dc.identifier.uri http://hdl.handle.net/10230/61060
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Cell Death Dis. 2024 May 31;15(5):382
  • dc.rights © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Apoptosis
  • dc.subject.keyword Autophagy
  • dc.subject.keyword Induced pluripotent stem cells
  • dc.subject.keyword Metabolomics
  • dc.subject.keyword Neurodegenerative diseases
  • dc.title Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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