Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is caused by progerin, an internally truncated prelamin A that does not undergo the ZMPSTE24 processing step that releases prelamin A's farnesylated carboxyl terminus; consequently, progerin remains farnesylated. Progerin and full-length farnesyl-prelamin A are equivalent in their abilities to disrupt the nuclear lamina and trigger nuclear membrane ruptures and cell death, but they differ markedly in their abilities to cause arterial pathology. In HGPS mice (Lmna(G609G)), progerin causes loss of aortic smooth muscle cells (SMCs) by 12 weeks, whereas farnesyl-prelamin A in Zmpste24(-/-) mice does not trigger SMC loss-even at 21 weeks. In young mice, farnesyl-prelamin A levels in Zmpste24(-/-) aortas and progerin levels in Lmna(G609G) aortas are identical; however, progerin levels in Lmna(G609G) aortas increase progressively with age, whereas farnesyl-prelamin A levels in Zmpste24(-/-) aortas remain the same or decline. SMC loss in Zmpste24(-/-) aortas occurs only with supraphysiologic levels of prelamin A synthesis (mimicking the accumulation of progerin). AKT activity (which mediates prelamin A phosphorylation and triggers prelamin A turnover) is lower in Lmna(G609G) aortas than in wild-type or Zmpste24(-/-) aortas. Our studies show that the progressive accumulation of progerin in the aorta underlies the arterial pathology in HGPS.