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Progerin elicits disease phenotypes of progeria in mice whether or not it is farnesylated
Shao H Yang1, Douglas A Andres, H Peter Spielmann
1Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, California, USA.
The Journal of Clinical Investigation
|September 5, 2008
Summary
Hutchinson-Guilford progeria syndrome (HGPS) is caused by progerin. This study shows that even without farnesyl anchors, progerin causes HGPS-like symptoms, suggesting limitations for farnesylation inhibition therapies.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Hutchinson-Guilford progeria syndrome (HGPS) is a rare premature aging disease.
- HGPS is caused by the accumulation of toxic progerin, a mutant form of prelamin A.
- Progerin's farnesyl lipid anchor is implicated in disease pathogenesis.
Purpose of the Study:
- To investigate the role of non-farnesylated progerin in HGPS pathogenesis.
- To determine if inhibiting protein farnesylation is a sufficient therapeutic strategy for HGPS.
Main Methods:
- Creation of knockin mice expressing non-farnesylated progerin (LmnanHG/+).
- Comparison of disease phenotypes in LmnanHG/+ mice with those of HGPS mice (LmnaHG/+).
- Analysis of nuclear shape abnormalities in mouse embryonic fibroblasts (MEFs) from both genotypes.
Main Results:
- LmnanHG/+ mice exhibited HGPS-like disease phenotypes, albeit milder than LmnaHG/+ mice.
- Fewer misshapen nuclei were observed in MEFs derived from LmnanHG/+ mice.
- Lower steady-state levels of progerin were detected in LmnanHG/+ mice.
Conclusions:
- Non-farnesylated progerin can elicit HGPS disease phenotypes.
- While farnesylation inhibition shows therapeutic promise, it may be limited as progerin is pathogenic regardless of its farnesylation status.
