Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a progeroid disorder characterized by multiple aging-like phenotypes, including disease in large arteries. HGPS is caused by an internally truncated prelamin A (progerin) that cannot undergo the ZMPSTE24-mediated processing step that converts farnesyl-prelamin A to mature lamin A; consequently, progerin retains a carboxyl-terminal farnesyl lipid anchor. In cultured cells, progerin and full-length farnesyl-prelamin A (produced in Zmpste24 -/- cells) form an abnormal nuclear lamin meshwork accompanied by nuclear membrane ruptures and cell death; however, these proteins differ in their capacity to cause arterial disease. In a mouse model of HGPS (Lmna G609G), progerin causes loss of aortic smooth muscle cells (SMCs) by ~12 weeks of age. In contrast, farnesyl-prelamin A in Zmpste24 -/- mice does not cause SMC loss-even at 21 weeks of age. In young mice, aortic levels of farnesyl-prelamin A in Zmpste24 -/- mice and aortic levels of progerin in Lmna G609G/+ mice are the same. However, the levels of progerin and other A-type lamins increase with age in Lmna G609G/+ mice, whereas farnesyl-prelamin A and lamin C levels in Zmpste24 -/- mice remain stable. Lmna transcript levels are similar, implying that progerin influences nuclear lamin turnover. We identified a likely mechanism. In cultured SMCs, the phosphorylation of Ser-404 by AKT (which triggers prelamin A degradation) is reduced in progerin. In mice, AKT activity is significantly lower in Lmna G609G/+ aortas than in wild-type or Zmpste24 -/- aortas. Our studies identify that the accumulation of progerin in Lmna G609G aortas underlies the hallmark arterial pathology in HGPS.