Cockayne syndrome mice reflect human kidney disease and are defective in de novo NAD biosynthesis
Cockayne Syndrome (CS) is a premature aging disorder caused by mutations in the CSA and CSB genes involved in DNA metabolism and other cellular processes. CS patients display many features including premature aging, neurodegeneration, and kidney abnormalities. Nicotinamide dinucleotide (NAD<sup>+</sup>) deprivation has been observed in CS patient-derived cells. NAD<sup>+</sup> has essential roles in regulating cellular health, stress responses, and renal homeostasis. While kidney dysfunction is a common feature in CS patients, its molecular pathogenesis is not understood. Here, we report that severe kidney pathology is present in CS A and B mice. We find that the NAD<sup>+</sup> biosynthetic pathways are impaired in kidneys from these mice. Using human renal tubular epithelial cells, we show that CSA/B downregulation causes persistent activation of the ATF3 transcription factor on the quinolinate phosphoribosyl transferase gene locus, a rate-limiting enzyme in de novo NAD<sup>+</sup> biosynthesis in the kidney, causing impaired transcription and deficient NAD<sup>+</sup> homeostasis.
Authors
- Briana A. Santo (ORCID: https://orcid.org/0000-0001-8850-2985)
- Komal Pekhale (ORCID: https://orcid.org/0000-0002-6372-3690)
- Deborah L. Croteau (ORCID: https://orcid.org/0000-0002-6094-4084)
- Vinod Tiwari (ORCID: https://orcid.org/0000-0003-2341-0953)
- Avi Z. Rosenberg (ORCID: https://orcid.org/0000-0003-2356-950X)
- Mansoor Hussain (ORCID: https://orcid.org/0000-0003-4260-2256)
- Xiaoxin X. Wang (ORCID: https://orcid.org/0000-0001-9205-6228)
- Xiaoping Yang (ORCID: https://orcid.org/0000-0003-1952-7227)
- Moshe Levi (ORCID: https://orcid.org/0000-0001-6403-2261)
- Christy C. Bridges (ORCID: https://orcid.org/0000-0003-1603-1445)
- Vilhelm A. Bohr (ORCID: https://orcid.org/0000-0003-4823-6429)
- Jong-Hyuk Lee
- Tomasz Kulikowicz
Institutions
- University of Copenhagen (DK)
- Johns Hopkins University (US)
- Mercer University (US)
- Georgetown University (US)
- Johns Hopkins Medicine (US)
- Georgetown University Medical Center (US)
- Mercer University Health Sciences Center (US)
- Institute on Aging (US)
- National Institute on Aging (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Cell Death and Differentiation
- Published
- 2025-05-15
- DOI
- https://doi.org/10.1038/s41418-025-01522-7
- Citations
- 1
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Novo Nordisk Fonden
- National Institutes of Health