A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria.

Abstract

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.

• Authors: Loren G Fong, David Frost, Margarita Meta, Xin Qiao, Shao H Yang, Catherine Coffinier, Stephen G Young
• Journal: Science (New York, N.Y.) (Science) Vol. 311 Issue 5767 Pg. 1621-3 (Mar 17 2006) ISSN: 1095-9203 [Electronic] United States
• PMID: 16484451 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABT-100
• Enzyme Inhibitors
• Imidazoles
• Lamin Type A
• Membrane Proteins
• Nuclear Proteins
• Protein Precursors
• prelamin A
• Farnesyltranstransferase
• Metalloendopeptidases
• Zmpste24 protein, mouse

Topics

• Animals
• Body Weight (drug effects)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Farnesyltranstransferase (antagonists & inhibitors)
• Female
• Hand Strength
• Imidazoles (pharmacology, therapeutic use)
• Lamin Type A
• Male
• Membrane Proteins (deficiency, genetics)
• Metalloendopeptidases (deficiency, genetics)
• Mice
• Nuclear Proteins (metabolism)
• Progeria (drug therapy, physiopathology)
• Protein Precursors (metabolism)
• Protein Prenylation (drug effects)
• Rib Fractures (prevention & control)
• Survival Rate