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Grant support

We are grateful to E. Bennet for technical assistance; H. Salmonowicz for graphical design; N. Watson, G. Nelson, and Newcastle Bioimaging Unit for imaging support; and ChromaDex Inc. for providing NR chloride.

Analysis of institutional authors

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

Publicated to:Cell Death & Disease. 15 (5): 382- - 2024-05-31 15(5), DOI: 10.1038/s41419-024-06770-y

Authors: Kataura, Tetsushi; Sedlackova, Lucia; Sun, Congxin; Kocak, Gamze; Wilson, Niall; Banks, Peter; Hayat, Faisal; Trushin, Sergey; Trushina, Eugenia; Maddocks, Oliver D K; Oblong, John E; Miwa, Satomi; Imoto, Masaya; Saiki, Shinji; Erskine, Daniel; Migaud, Marie E; Sarkar, Sovan; Korolchuk, Viktor I

Affiliations

Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, Barcelona, Spain - Author
Juntendo Univ, Grad Sch Med, Div Dev Autophagy Modulating Drugs, Bunkyo, Tokyo 1138421, Japan - Author
Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, 200 First St SW, Rochester, MN 55905 USA - Author
Mayo Clin, Dept Neurol, 200 First St SW, Rochester, MN 55905 USA - Author
Newcastle Univ, Biosci Inst, Fac Med Sci, Newcastle Upon Tyne NE4 5PL, England - Author
Newcastle Univ, Translat & Clin Res Inst, Newcastle Upon Tyne NE1 7RU, England - Author
Procter & Gamble Co, Cincinnati, OH 45040 USA - Author
Univ Birmingham, Inst Canc & Genom Sci, Inst Biomed Res, Coll Med & Dent Sci, Birmingham B15 2TT, England - Author
Univ Glasgow, Inst Canc Sci, Glasgow G61 1QH, Scotland - Author
Univ S Alabama, Mitchell Canc Inst, FP Whiddon Coll Med, Dept Pharmacol, Mobile, AL 36604 USA - Author
Univ Tsukuba, Inst Med, Dept Neurol, Tsukuba, Ibaraki 3058575, Japan - Author
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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.

Keywords
CholesterolHomeostasisImpaired autophagyMechanismsMitochondrial dysfunctionMitophagyNeural cellsPinkReveals

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Cell Death & Disease due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 33/205, thus managing to position itself as a Q1 (Primer Cuartil), in the category Cell Biology.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-05-10:

  • WoS: 1
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-10:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 12.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 12 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 7.3.
  • The number of mentions on the social network X (formerly Twitter): 10 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Japan; United Kingdom; United States of America.

the author responsible for correspondence tasks has been Sedlackova, Lucia.