title: Targeting isoprenylcysteine methylation ameliorates disease in a mouse model of progeria.
abstract: 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.
authors.affiliation: Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-41390 Gothenburg, Sweden.
authors.forename: Mohamed X
authors.initials: MX
authors.lastname: Ibrahim
authors.forename: Volkan I
authors.initials: VI
authors.lastname: Sayin
authors.forename: Murali K
authors.initials: MK
authors.lastname: Akula
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.forename: Loren G
authors.initials: LG
authors.lastname: Fong
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Martin O
authors.initials: MO
authors.lastname: Bergo
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D018737:Hand Strength; D006801:Humans; D034904:Lamin Type A; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000378:metabolism; D011371:Progeria / Q000503:physiopathology / Q000628:therapy*; D011496:Protein Methyltransferases / Q000235:genetics* / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015430:Weight Gain / Q000235:genetics
chemical_list: D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse