Nature communications, 2018-04, Vol.9 (1), p.1700-14, Article 1700
2018
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- Autor(en) / Beteiligte
- Titel
- Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome
- Ist Teil von
- Nature communications, 2018-04, Vol.9 (1), p.1700-14, Article 1700
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting the nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence. Therapeutic approaches targeting farnesylation or aiming to reduce progerin levels have provided only partial health improvements. Recently, we identified Remodelin, a small-molecule agent that leads to amelioration of HGPS cellular defects through inhibition of the enzyme N-acetyltransferase 10 (NAT10). Here, we show the preclinical data demonstrating that targeting NAT10 in vivo, either via chemical inhibition or genetic depletion, significantly enhances the healthspan in a Lmna G609G HGPS mouse model. Collectively, the data provided here highlights NAT10 as a potential therapeutic target for HGPS. Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-018-03770-3Titel-ID: cdi_doaj_primary_oai_doaj_org_article_b33496fa8a17473f945f0a89142ec415
- Format
- –
- Schlagworte
- 13, 13/1, 13/106, 13/51, 14/63, 45/41, 49/39, 49/91, 631/208/211, 631/443/7, 64/60, 692/308/153, Acetyltransferase, Age, Aging, Aging, Premature - drug therapy, Aging, Premature - genetics, Aging, Premature - mortality, Aging, Premature - pathology, Animals, Biochemistry, Biocompatibility, Cardiovascular diseases, Chemical Sciences, Chromatin, Coronary vessels, Damage accumulation, Deoxyribonucleic acid, Disease Models, Animal, DNA, DNA damage, DNA Damage - drug effects, DNA Damage - genetics, Female, Fibroblasts, Genomic Instability - drug effects, Genomic Instability - genetics, Humanities and Social Sciences, Humans, Hydrazones - pharmacology, Hydrazones - therapeutic use, Inhibition, Kaplan-Meier Estimate, Lamin Type A - genetics, Life Sciences, Male, Medical research, Mice, Mice, Inbred C57BL, Mice, Knockout, multidisciplinary, Musculoskeletal system, Mutation, N-Acetyltransferase, N-Terminal Acetyltransferase A - antagonists & inhibitors, N-Terminal Acetyltransferase A - genetics, N-Terminal Acetyltransferase A - metabolism, N-Terminal Acetyltransferases, Progeria, Progeria - drug therapy, Progeria - genetics, Progeria - mortality, Progeria - pathology, Science, Science (multidisciplinary), Senescence, Smooth muscle, Therapeutic applications, Thiazoles - pharmacology, Thiazoles - therapeutic use