Farnesylated
prelamin A is a processing intermediate produced in the
lamin A maturation pathway. Accumulation of a truncated farnesylated
prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford
progeria. Progerin elicits toxic effects in cells, leading to
chromatin damage and cellular senescence and ultimately causes skin and endothelial defects,
bone resorption,
lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying
prelamin A turnover is critical for the development of clinically effective
protein inhibitors that can avoid accumulation to toxic levels without impairing
lamin A/C expression, which is essential for normal
biological functions. Little is known about specific molecules that may target farnesylated
prelamin A to elicit protein degradation. Here, we report the discovery of
rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases
protein levels through a mechanism involving autophagic degradation.
Rapamycin treatment of
progeria cells lowers progerin, as well as wild-type
prelamin A levels, and rescues the
chromatin phenotype of cultured fibroblasts, including
histone methylation status and BAF and
LAP2alpha distribution patterns. Importantly,
rapamycin treatment does not affect
lamin C protein levels, but increases the relative expression of the
prelamin A endoprotease ZMPSTE24. Thus,
rapamycin, an
antibiotic belonging to the class of
macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated
prelamin A accumulation, and restore
chromatin dynamics in progeroid
laminopathies.