期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 102, 期 36, 页码 12873-12878出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0505767102
关键词
aging; Hutchinson-Gilford progeria syndrome; lamin; restrictive dermopathy; ZMPSTE24
资金
- NCI NIH HHS [R01 CA099506, CA099506] Funding Source: Medline
- NIAID NIH HHS [R01 AI054384, AI054384] Funding Source: Medline
- NIAMS NIH HHS [R01 AR050200, AR050200] Funding Source: Medline
Defects in the biogenesis of lamin A from its farnesylated precursor, prelamin A, lead to the accumulation of prelamin A at the nuclear envelope, cause misshapen nuclei, and result in progeroid syndromes. A deficiency in ZMPSTE24, a protease involved in prelamin A processing, leads to prelamin A accumulation, an absence of mature lamin A, misshapen nuclei, and a lethal perinatal progeroid syndrome: restrictive dermopathy (RD). Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutant prelamin A that cannot be processed to lamin A. The hallmark cellular abnormality in RD and HGPS is misshapen nuclei. We hypothesized that the farnesylation of prelamin A is important for its targeting to the nuclear envelope in RD and HGPS and that blocking farnesylation would ameliorate the nuclear shape abnormalities. Indeed, when RD fibroblasts were treated with a farnesyltransferase inhibitor (FTI), prelamin A was partially mislocalized away from the nuclear envelope, and the frequency of nuclear shape abnormalities was reduced (P < 0.0001). A FTI also mislocalized prelamin A and improved nuclear shape in Zmpste24-deficient mouse embryonic fibroblasts (P < 0.0001) and improved nuclear shape in human HGPS fibroblasts (P < 0.0001). Most remarkably, a FTI significantly improved nuclear shape in two fibroblast cell lines from atypical progeria patients with lamin A missense mutations in the absence of prelamin A accumulation (P = 0.0003 and P < 0.0001). These findings establish a paradigm for ameliorating the most obvious cellular pathology in lamin-related progeroid syndromes and suggest a potential strategy for treating these diseases.
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