title: Perturbation of wild-type lamin A metabolism results in a progeroid phenotype.
abstract: Mutations in the lamin A/C gene cause the rare genetic disorder Hutchinson-Gilford progeria syndrome (HGPS). The prevalent mutation results in the production of a mutant lamin A protein with an internal 50 amino acid deletion which causes a cellular aging phenotype characterized by growth defects, limited replicative lifespan, and nuclear membrane abnormalities. However, the relevance of these findings to normal human aging is unclear. In this study, we demonstrate that increased levels of wild-type lamin A in normal human cells result in decreased replicative lifespan and nuclear membrane abnormalities that lead to apoptotic cell death and senescence in a manner that is strongly reminiscent of the phenotype shown by HGPS cells. In contrast to the accelerated aging defects observed in HGPS cells, the progeroid phenotype resulting from increased expression of wild-type lamin A can be rescued by overexpression of ZMPSTE24, the metalloproteinase responsible for the removal of the farnesylated carboxyl terminal region of lamin A. Furthermore, farnesyltransferase inhibitors also serve to reverse the progeroid phenotype resulting from increased lamin A expression. Significantly, cells expressing elevated levels of lamin A display abnormal lamin A localization and similar alterations in the nuclear distribution of lamin A are also observed in cells from old-age individuals. These data demonstrate that the metabolism of wild-type lamin A is delicately poised and even in the absence of disease-linked mutations small perturbations in this system are sufficient to cause prominent nuclear defects and result in a progeroid phenotype.
authors: Department of Molecular Microbiology and Immunology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors: Jose
authors: J
authors: Candelario
authors: Sivasubramaniam
authors: S
authors: Sudhakar
authors: Sonia
authors: S
authors: Navarro
authors: Sita
authors: S
authors: Reddy
authors: Lucio
authors: L
authors: Comai
mesh_terms: D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D017209:Apoptosis; D002467:Cell Nucleus; D002478:Cells, Cultured; D016922:Cellular Senescence; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D011371:Progeria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D034904:Lamin Type A; D008565:Membrane Proteins; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human