title: Blocking protein farnesylation improves nuclear shape abnormalities in keratinocytes of mice expressing the prelamin A variant in Hutchinson-Gilford progeria syndrome.
abstract: Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated aging disorder caused by mutations in LMNA leading to expression of a truncated prelamin A variant termed progerin. Whereas a farnesylated polypeptide is normally removed from the carboxyl-terminus of prelamin A during endoproteolytic processing to lamin A, progerin lacks the cleavage site and remains farnesylated. Cultured cells from human subjects with HGPS and genetically modified mice expressing progerin have nuclear morphological abnormalities, which are reversed by inhibitors of protein farnesylation. In addition, treatment with protein farnesyltransferase inhibitors improves whole animal phenotypes in mouse models of HGPS. However, improvement in nuclear morphology in tissues after treatment of animals has not been demonstrated. We therefore treated transgenic mice that express progerin in epidermis with the protein farnesyltransferase inhibitor FTI-276 or a combination of pravastatin and zoledronate to determine if they reversed nuclear morphological abnormalities in tissue. Immunofluorescence microscopy and "blinded" electron microscopic analysis demonstrated that systemic administration of FTI-276 or pravastatin plus zoledronate significantly improved nuclear morphological abnormalities in keratinocytes of transgenic mice. These results show that pharmacological blockade of protein prenylation reverses nuclear morphological abnormalities that occur in HGPS in vivo. They further suggest that skin biopsy may be useful to determine if protein farnesylation inhibitors are exerting effects in subjects with HGPS in clinical trials.
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Wang
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ostlund
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
mesh_terms: D000818:Animals; D001706:Biopsy; D002467:Cell Nucleus / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004164:Diphosphonates / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D004817:Epidermis / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D015603:Keratinocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D034904:Lamin Type A; D008715:Methionine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D053140:Organelle Shape / Q000187:drug effects; D017035:Pravastatin / Q000008:administration & dosage / Q000627:therapeutic use; D011371:Progeria / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects*; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D004791:Enzyme Inhibitors; C404062:FTI 276; D007093:Imidazoles; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D000077211:Zoledronic Acid; D008715:Methionine; D051231:Farnesyltranstransferase; D017035:Pravastatin