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Cell Death Differ., 15 May 2025 | https://doi.org/10.1038/s41418-025-01522-7
Cockayne syndrome mice reflect human kidney disease and are defective in de novo NAD biosynthesis
Komal Pekhale 1,2, Vinod Tiwari 1, Mansoor Hussain 1, Christy C. Bridges 3, Deborah L. Croteau 1,4, Moshe Levi 5, Avi Z. Rosenberg 6, Briana Santo 7, Xiaoping Yang 6, Tomasz Kulikowicz 1, Xiaoxin X. Wang 5, Jong-Hyuk Lee 1,3,8,10,* and Vilhelm A. Bohr 1,9,10,*
1DNA repair section, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
2Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
4Computational Biology & Genomics Core, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
5Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
6Department of Pathology Johns Hopkins University School of Medicine, Baltimore, MD, USA.
7Johns Hopkins University School of Medicine, Baltimore, MD, USA.
8Center for Gerontology, Mercer University, Macon, GA 31207, USA.
9Danish Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.
10These authors contributed equally: Jong-Hyuk Lee, Vilhelm A. Bohr.
2Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
4Computational Biology & Genomics Core, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
5Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
6Department of Pathology Johns Hopkins University School of Medicine, Baltimore, MD, USA.
7Johns Hopkins University School of Medicine, Baltimore, MD, USA.
8Center for Gerontology, Mercer University, Macon, GA 31207, USA.
9Danish Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.
10These authors contributed equally: Jong-Hyuk Lee, Vilhelm A. Bohr.
*Corresponding authors: correspondence to Jong-Hyuk Lee or Vilhelm A. Bohr
Abstract
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+) deprivation has been observed in CS patient-derived cells. NAD+ 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+ 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+ biosynthesis in the kidney, causing impaired transcription and deficient NAD+ homeostasis.
논문정보
- Research article
- 2025년 05월 (BRIC 등록일 2025-05-21)
- 국외 연구진
- 생명과학 > 분자생물학
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