Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

Abstract

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 LAP2α 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.

Centenarian lamins: rapamycin targets in longevity

“…Because rapamycin, a drug known to extend lifespan in mouse and C. elegans, affects prelamin A stability (Cenni et al, 2011b;Graziotto et al, 2012) and triggers both nuclear import and activation of 53BP1 (Bandhakavi et al, 2010;Pospelova et al, 2012), we tested the effect of rapamycin in fibroblasts. As shown in Fig.…”

Emerging perspectives on laminopathies

“…However, different therapeutic strategies are developing 91 as pharmacological and gene approaches for both systemic and nonsystemic laminopathies. 92 Prelamin A elicits toxic effects in cells, leading to chromatin damage and cellular senescence, ultimately causing accelerated skin aging. 92 Rapamycin, an antibiotic belonging to the class of macrolides, is able to inhibit progerin, dramatically and selectively decreasing protein levels through a mechanism involving autophagic degradation.…”

“…92 Prelamin A elicits toxic effects in cells, leading to chromatin damage and cellular senescence, ultimately causing accelerated skin aging. 92 Rapamycin, an antibiotic belonging to the class of macrolides, is able to inhibit progerin, dramatically and selectively decreasing protein levels through a mechanism involving autophagic degradation. Progeria cells treated by rapamycin show lower levels of progerin and wild-type prelamin A, suggesting the drug can serve as a therapeutic tool to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics.…”

“…Progeria cells treated by rapamycin show lower levels of progerin and wild-type prelamin A, suggesting the drug can serve as a therapeutic tool to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics. 92,93 Quite promising results have been found with the use of farnesyltransferase inhibitors (FTIs). Initially developed as a target drug for an oncogenic RAS gene, FTIs have been shown to block the enzyme responsible for the farnesylation step on prelamin A in HGPS.…”

HP1α mediates defective heterochromatin repair and accelerates senescence inZmpste24-deficient cells

“…[6][7][8] Reducing farnesyl prelamin A accumulation on the nuclear lamina by farnesyltransferase inhibitor (FTI) or accelerating autophagic degradation of progerin through rapamycin ameliorates cellular senescence in HGPS cells and premature aging in Zmpste24-deficient mice. [9][10][11][12][13] Further studies revealed interphase aneuploidy chromatin, loss or aggregation of peripheral heterochromatin, abnormally clustered centromeres, and mislocalized telomeres in fibroblasts isolated from HGPS patients and Zmpste24-deficient mice.…”