Details

Autor(en) / Beteiligte

• Yang, Shao H
• Andres, Douglas A
• Spielmann, H Peter
• Young, Stephen G
• Fong, Loren G

Titel

Progerin elicits disease phenotypes of progeria in mice whether or not it is farnesylated

Ist Teil von

• The Journal of clinical investigation, 2008-10, Vol.118 (10), p.3291-3300

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2008

Quelle

MEDLINE

Beschreibungen/Notizen

• Hutchinson-Gilford progeria syndrome (HGPS), a rare disease that results in what appears to be premature aging, is caused by the production of a mutant form of prelamin A known as progerin. Progerin retains a farnesyl lipid anchor at its carboxyl terminus, a modification that is thought to be important in disease pathogenesis. Inhibition of protein farnesylation improves the hallmark nuclear shape abnormalities in HGPS cells and ameliorates disease phenotypes in mice harboring a knockin HGPS mutation (LmnaHG/+). The amelioration of disease, however, is incomplete, leading us to hypothesize that nonfarnesylated progerin also might be capable of eliciting disease. To test this hypothesis, we created knockin mice expressing nonfarnesylated progerin (LmnanHG/+). LmnanHG/+ mice developed the same disease phenotypes observed in LmnaHG/+ mice, although the phenotypes were milder, and mouse embryonic fibroblasts (MEFs) derived from these mice contained fewer misshapen nuclei. The steady-state levels of progerin in LmnanHG/+ MEFs and tissues were lower, suggesting a possible explanation for the milder phenotypes. These data support the concept that inhibition of protein farnesylation in progeria could be therapeutically useful but also suggest that this approach may be limited, as progerin elicits disease phenotypes whether or not it is farnesylated.