Progeria, the nucleolus and farnesyltransferase inhibitors.
HGPS (Hutchinson-Gilford progeria syndrome) is a rare genetic disease affecting children causing them to age and die prematurely. The disease is typically due to a point mutation in the coding sequence for the nuclear intermediate-type filament protein lamin A and gives rise to a dominant-negative splice variant named progerin. Accumulation of progerin within nuclei causes disruption to nuclear structure, causes and premature replicative senescence and increases apoptosis. Now it appears that accumulation of progerin may have more widespread effects than previously thought since the demonstration that the presence and distribution of some nucleolar proteins are also adversely affected in progeria cells. One of the major breakthroughs both in the lamin field and for this syndrome is that many of the cellular defects observed in HGPS patient cells and model systems can be restored after treatment with a class of compounds known as FTIs (farnesyltransferase inhibitors). Indeed, it is demonstrated that FTI-277 is able to completely restore nucleolar antigen localization in treated progeria cells. This is encouraging news for the HGPS patients who are currently undergoing clinical trials with FTI treatment.
Mehta
Ishita S
IS
Laboratory of Nuclear and Genomic Health, Centre for Cell and Chromosome Biology, Division of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge UB8 3PH, UK.
Bridger
Joanna M
JM
Kill
Ian R
IR
D002466:Cell Nucleolus / Q000378:metabolism*; D002648:Child; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism; D008715:Methionine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011371:Progeria / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
D002868:Chromosomal Proteins, Non-Histone; D004791:Enzyme Inhibitors; C096856:FTI 277; D034904:Lamin Type A; C047458:fibrillarin; D008715:Methionine; D051231:Farnesyltranstransferase