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

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 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 ( ), progerin causes loss of aortic smooth muscle cells (SMCs) by ~12 weeks of age. In contrast, farnesyl-prelamin A in mice does not cause SMC loss-even at 21 weeks of age. In young mice, aortic levels of farnesyl-prelamin A in mice and aortic levels of progerin in mice are the same. However, the levels of progerin and other A-type lamins increase with age in mice, whereas farnesyl-prelamin A and lamin C levels in mice remain stable. 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 aortas than in wild-type or aortas. Our studies identify that the accumulation of progerin in aortas underlies the hallmark arterial pathology in HGPS.