The Accumulation of Progerin Underlies the Loss of Aortic Smooth Muscle Cells in Hutchinson-Gilford Progeria Syndrome

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 (LmnaG609G), 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 LmnaG609G/+ mice are the same. However, the levels of progerin and other A-type lamins increase with age in LmnaG609G/+ 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 LmnaG609G/+ aortas than in wild-type or Zmpste24-/- aortas. Our studies identify that the accumulation of progerin in LmnaG609G aortas underlies the hallmark arterial pathology in HGPS.

One Sentence SummaryThe age-related accumulation of progerin in smooth muscle cells (SMCs) explains the loss of arterial SMCs in Hutchinson-Gilford progeria syndrome.