Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 12, Pages 4949-4954Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0611640104
Keywords
aging; laminopathy; progerin
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Funding
- NIA NIH HHS [R00 AG029761, K99 AG029761-01A1, R00 AG029761-02, K99 AG029761] Funding Source: Medline
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Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by dramatic premature aging. Classic HGIPS is caused by a de novo point mutation in exon 11 (residue 1824, C -> T) of the LMNA gene, activating a cryptic splice donor and resulting in a mutant lamin A (LA) protein termed progerin/LA Delta 50 that lacks the normal cleavage site to remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated progerin/LA Delta 50 anchors to the nuclear membrane and causes characteristic nuclear blebbing. Progerin/LA Delta 50's localization and behavior during mitosis, however, are completely unknown. Here, we report that progerin/LA Delta 50 mislocalizes into insoluble cytoplasmic aggregates and membranes during mitosis and causes abnormal chromosome segregation and binucleation. These phenotypes are largely rescued with either farnesyltransferase inhibitors or a farnesylation-incompetent mutant progerin/LA Delta 50. Furthermore, we demonstrate that small amounts of progerin/LAA50 exist in normal fibroblasts, and a significant percentage of these progerin/LA Delta 50-expressing normal cells are binucleated, implicating progerin/LAA50 as causing similar mitotic defects in the normal aging process. Our findings present evidence of mitotic abnormality in HGPS and may shed light on the general phenomenon of aging.
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