Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome.

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging disease resulting from a mutation in the LMNA gene, which encodes nuclear lamins A and C. Lamin A is synthesized as a precursor (prelamin A) with a C-terminal CaaX motif that undergoes farnesylation, endoproteolytic cleavage, and carboxylmethylation. Prelamin A is subsequently internally cleaved by the zinc metalloprotease Ste24 (Zmpste24) protease, which removes the 15 C-terminal amino acids, including the CaaX modifications, to yield mature lamin A. HGPS results from a dominant mutant form of prelamin A (progerin) that has an internal deletion of 50 aa near the C terminus that includes the Zmpste24 cleavage site and blocks removal of the CaaX-modified C terminus. Fibroblasts from HGPS patients have aberrant nuclei with irregular shapes, which we hypothesize result from the abnormal persistence of the farnesyl and/or carboxylmethyl CaaX modifications on progerin. If this hypothesis is correct, inhibition of CaaX modification by mutation or pharmacological treatment should alleviate the nuclear morphology defect. Consistent with our hypothesis, we find that expression in HeLa cells of GFP-progerin or an uncleavable form of prelamin A with a Zmpste24 cleavage site mutation induces the formation of abnormal nuclei similar to those in HGPS fibroblasts. Strikingly, inhibition of farnesylation pharmacologically with the farnesyl transferase inhibitor rac-R115777 or mutationally by alteration of the CaaX motif dramatically reverses the abnormal nuclear morphology. These results suggest that farnesyl transferase inhibitors represent a possible therapeutic option for individuals with HGPS and/or other laminopathies due to Zmpste24 processing defects.

• Authors: Monica P Mallampalli, Gregory Huyer, Pravin Bendale, Michael H Gelb, Susan Michaelis
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 40 Pg. 14416-21 (Oct 04 2005) ISSN: 0027-8424 [Print] United States
• PMID: 16186497 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Lamin Type A
• Lipoproteins
• Membrane Proteins
• Nuclear Proteins
• Protein Precursors
• Quinolones
• prelamin A
• Green Fluorescent Proteins
• Metalloproteases
• Metalloendopeptidases
• ZMPSTE24 protein, human
• tipifarnib

Topics

• Amino Acid Motifs (genetics)
• Blotting, Western
• Cell Nucleus (pathology)
• Fibroblasts (cytology)
• Green Fluorescent Proteins (metabolism)
• HeLa Cells
• Humans
• Lamin Type A
• Lipoproteins (genetics, metabolism)
• Membrane Proteins (genetics, metabolism)
• Metalloendopeptidases
• Metalloproteases (genetics, metabolism)
• Mutation (genetics)
• Nuclear Proteins (genetics, metabolism)
• Progeria (genetics, pathology)
• Protein Precursors (genetics, metabolism)
• Protein Prenylation (drug effects, genetics)
• Quinolones (pharmacology)