Title |
Defective Lamin A-Rb Signaling in Hutchinson-Gilford Progeria Syndrome and Reversal by Farnesyltransferase Inhibition
|
---|---|
Published in |
PLOS ONE, June 2010
|
DOI | 10.1371/journal.pone.0011132 |
Pubmed ID | |
Authors |
Jackleen Marji, Seán I. O'Donoghue, Dayle McClintock, Venkata P. Satagopam, Reinhard Schneider, Desiree Ratner, Howard J. Worman, Leslie B. Gordon, Karima Djabali |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 1 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 2 | 2% |
United Kingdom | 1 | 1% |
France | 1 | 1% |
Japan | 1 | 1% |
Poland | 1 | 1% |
Unknown | 83 | 93% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 20 | 22% |
Student > Bachelor | 14 | 16% |
Student > Master | 11 | 12% |
Researcher | 10 | 11% |
Professor | 6 | 7% |
Other | 17 | 19% |
Unknown | 11 | 12% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 46 | 52% |
Biochemistry, Genetics and Molecular Biology | 11 | 12% |
Medicine and Dentistry | 10 | 11% |
Pharmacology, Toxicology and Pharmaceutical Science | 3 | 3% |
Economics, Econometrics and Finance | 1 | 1% |
Other | 4 | 4% |
Unknown | 14 | 16% |