Defective Lamin A-Rb Signaling in Hutchinson-Gilford Progeria Syndrome and Reversal by Farnesyltransferase Inhibition

• Published in: PloS one Vol. 5; no. 6; p. e11132
• Main Authors: Marji, Jackleen, O'Donoghue, Seán I., McClintock, Dayle, Satagopam, Venkata P., Schneider, Reinhard, Ratner, Desiree, J. Worman, Howard, Gordon, Leslie B., Djabali, Karima
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.06.2010; Public Library of Science (PLoS)
• Subjects: Aging; Amino acids; Analysis; Animal models; Animals; Blotting, Western; Cell Biology/Cell Signaling; Cell Biology/Gene Expression; Cell Biology/Nuclear Structure and Function; Cell cycle; Clonal deletion; Complications; Cysteine; Defects; Deoxyribonucleic acid; Dermatology; Disease Models, Animal; DNA; Enzyme Inhibitors - pharmacology; Farnesyltransferase; Farnesyltranstransferase - antagonists & inhibitors; Fibroblasts; Fluorescent Antibody Technique, Indirect; Gene deletion; Gene expression; Gene mutation; Genes; Genetic aspects; Genome-Wide Association Study; Genomes; Gerontology; Humans; Inhibition; Intermediate filament proteins; Lamin Type A - metabolism; Lamins; Morphology; Musculoskeletal system; Mutation; Oligonucleotide Array Sequence Analysis; Pathogenesis; Pathology; Physiological aspects; Point mutation; Progeria; Progeria - metabolism; Protein farnesyltransferase; Proteins; Retinoblastoma Protein - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Science; Signal Transduction - drug effects; Signaling; Surgeons; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0011132

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by a de novo heterozygous point mutation G608G (GGC>GGT) within exon 11 of LMNA gene encoding A-type nuclear lamins. This mutation elicits an internal deletion of 50 amino acids in the carboxyl-terminus of prelamin A. The truncated protein, progerin, retains a farnesylated cysteine at its carboxyl terminus, a modification involved in HGPS pathogenesis. Inhibition of protein farnesylation has been shown to improve abnormal nuclear morphology and phenotype in cellular and animal models of HGPS. We analyzed global gene expression changes in fibroblasts from human subjects with HGPS and found that a lamin A-Rb signaling network is a major defective regulatory axis. Treatment of fibroblasts with a protein farnesyltransferase inhibitor reversed the gene expression defects. Our study identifies Rb as a key factor in HGPS pathogenesis and suggests that its modulation could ameliorate premature aging and possibly complications of physiological aging.