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Targeting Isoprenylcysteine Methylation Ameliorates Disease in a Mouse Model of Progeria

Methylation and Methuselah? Hutchinson-Gilford progeria syndrome (HGPS) and other prelamin A–associated progeroid disorders arise when farnesylated and methylated forms of prelamin A accumulate at the nuclear envelope. Ibrahim et al. (p. 1330, published online 16 May; see the Perspective by Johnson) show that reducing the activity of the isoprenylcysteine carboxyl methyltransferase (ICMT) mislocalizes prelamin A, triggers prelamin A–dependent AKT-mTOR signaling, and eliminates disease phenotypes in 30-week-old progeria model mice. Reduced ICMT expression increased the proliferation and delayed the premature senescence of progeria model mouse fibroblasts and cells from children with HGPS. Reduced protein methyltransferase activity improves progeria-like disease phenotypes. [Also see Perspective by Johnson] Several progeroid disorders, including Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (ZMPSTE24 deficiency), arise when a farnesylated and methylated form of prelamin A accumulates at the nuclear envelope. Here, we found that a hypomorphic allele of isoprenylcysteine carboxyl methyltransferase (ICMT) increased body weight, normalized grip strength, and prevented bone fractures and death in Zmpste24-deficient mice. The reduced ICMT activity caused prelamin A mislocalization within the nucleus and triggered prelamin A–dependent activation of AKT-mammalian target of rapamycin (mTOR) signaling, which abolished the premature senescence of Zmpste24-deficient fibroblasts. ICMT inhibition increased AKT-mTOR signaling and proliferation and delayed senescence in human HGPS fibroblasts but did not reduce the levels of misshapen nuclei in mouse and human cells. Thus, targeting ICMT might be useful for treating prelamin A–associated progeroid disorders.