Everolimus rescues multiple cellular defects in laminopathy-patient fibroblasts

被引:40
作者
DuBose, Amanda J. [1 ]
Lichtenstein, Stephen T. [1 ]
Petrash, Noreen M. [1 ]
Erdos, Michael R. [1 ]
Gordon, Leslie B. [2 ,3 ,4 ,5 ]
Collins, Francis S. [1 ]
机构
[1] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA
[2] Brown Univ, Hasbro Childrens Hosp, Dept Pediat, Providence, RI 02903 USA
[3] Brown Univ, Warren Alpert Med Sch, Providence, RI 02903 USA
[4] Boston Childrens Hosp, Dept Anesthesia, Boston, MA 02115 USA
[5] Harvard Med Sch, Boston, MA 02115 USA
关键词
everolimus; laminopathies; lamin; mTOR; progeria; HUTCHINSON-GILFORD-PROGERIA; FARNESYLTRANSFERASE INHIBITOR; NUCLEAR-ENVELOPE; LAMIN; RAPAMYCIN; MUTATIONS; DISEASE; FARNESYLATION; ARCHITECTURE; EXPRESSION;
D O I
10.1073/pnas.1802811115
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
LMNA encodes the A-type lamins that are part of the nuclear scaffold. Mutations in LMNA can cause a variety of disorders called laminopathies, including Hutchinson-Gilford progeria syndrome (HGPS), atypical Werner syndrome, and Emery-Dreifuss muscular dystrophy. Previous work has shown that treatment of HGPS cells with the mTOR inhibitor rapamycin or with the rapamycin analog everolimus corrects several of the phenotypes seen at the cellular level-at least in part by increasing autophagy and reducing the amount of progerin, the toxic form of lamin A that is overproduced in HGPS patients. Since other laminopathies also result in production of abnormal and potentially toxic lamin proteins, we hypothesized that everolimus would also be beneficial in those disorders. To test this, we applied everolimus to fibroblast cell lines from six laminopathy patients, each with a different mutation in LMNA. Everolimus treatment increased proliferative ability and delayed senescence in all cell lines. In several cell lines, we observed that with treatment, there is a significant improvement in nuclear blebbing, which is a cellular hallmark of HGPS and other lamin disorders. These preclinical results suggest that everolimus might have clinical benefit for multiple laminopathy syndromes.
引用
收藏
页码:4206 / 4211
页数:6
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