A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria.
Progerias are rare genetic diseases characterized by premature aging. Several progeroid disorders are caused by mutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural scaffolding for the cell nucleus. In progeria, the accumulation of farnesyl-prelamin A disrupts this scaffolding, leading to misshapen nuclei. Previous studies have shown that farnesyltransferase inhibitors (FTIs) reverse this cellular abnormality. We tested the efficacy of an FTI (ABT-100) in Zmpste24-deficient mice, a mouse model of progeria. The FTI-treated mice exhibited improved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age. These results suggest that FTIs may have beneficial effects in humans with progeria.
Fong
Loren G
LG
Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. lfong@mednet.ucla.edu
Frost
David
D
Meta
Margarita
M
Qiao
Xin
X
Yang
Shao H
SH
Coffinier
Catherine
C
Young
Stephen G
SG
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D018737:Hand Strength; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D034904:Lamin Type A; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D011371:Progeria / Q000188:drug therapy* / Q000503:physiopathology; D011498:Protein Precursors / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects; D012253:Rib Fractures / Q000517:prevention & control; D015996:Survival Rate
C503142:ABT-100; D004791:Enzyme Inhibitors; D007093:Imidazoles; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D051231:Farnesyltranstransferase; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse