Prelamin A Farnesylation and Progeroid Syndromes*

  title={Prelamin A Farnesylation and Progeroid Syndromes*},
  author={Stephen G. Young and Margarita D. Meta and Shao H. Yang and Loren G. Fong},
  journal={Journal of Biological Chemistry},
  pages={39741 - 39745}
Hutchinson-Gilford progeria syndrome (HGPS) is caused by a LMNA mutation that leads to the synthesis of a mutant prelamin A that is farnesylated but cannot be further processed to mature lamin A. A more severe progeroid disorder, restrictive dermopathy (RD), is caused by the loss of the prelamin A-processing enzyme, ZMPSTE24. The absence of ZMPSTE24 prevents the endoproteolytic processing of farnesyl-prelamin A to mature lamin A and leads to the accumulation of farnesyl-prelamin A. In both HGPS… 

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A Wrinkle in Time: Premature Aging in HGPS and RD
With continued research, more can be learned about the normal aging process, which could be applied in understanding progeroid syndromes and developing alternative treatments.
The clinical characteristics of this disease, the underlying mutation in the lamin A (LMNA) gene that results in this phenotype and the recent advances in treatment strategies are summarized.
A-type lamins and Hutchinson-Gilford progeria syndrome: pathogenesis and therapy.
Recent advances into the pathogenic mechanisms underlying HGPS, the main murine models of the disease, and the therapeutic strategies developed in cellular and animal models with the aim of reducing the accumulation of farnesylated-progerin are discussed, as well as their use in clinical trials of HGPS.
Intermittent treatment with farnesyltransferase inhibitor and sulforaphane improves cellular homeostasis in Hutchinson-Gilford progeria fibroblasts.
Co-administration of both drugs exerts a synergistic and additive positive effect on autophagy activity but was cytotoxic to HGPS cells, and it is proposed that intermittent treatment with FTI and SFN separately might be a promising therapeutic avenue for children with HGPS.
Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice
These novel mice provide a robust model to study the effects of farnesylated prelamin A during physiological aging andcultured embryonic fibroblasts from LmnaL648R/l648R mice have aberrant nuclear morphology that is reversible by treatment with a protein farnesytransferase inhibitor.
Epithelial stem cells In Hutchinson-Gilford progeria syndrome
Novel findings are offered about the intricate molecular disease mechanisms underlying HGPS and RD, which include increased inflammation, prolonged expression of the lamin B receptor gene, and arrested skin development.
Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes
Two patients with extraordinarily severe forms of progeria caused by unusual mutations in LMNA are presented, and farnesyltransferase inhibitors may prove to be useful even when progerin expression levels are higher than those in typical HGPS patients.


Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes.
  • J. Toth, Shao H. Yang, L. Fong
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2005
Findings establish a paradigm for ameliorating the most obvious cellular pathology in lamin-related progeroid syndromes and suggest a potential strategy for treating these diseases.
Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation.
A gene-targeted mouse model of HGPS was created, genetically identical primary mouse embryonic fibroblasts were generated, and the effect of a farnesyltransferase inhibitor on nuclear blebbing was examined, suggesting a possible treatment strategy for HGPS.
Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome.
The results suggest that treatment with FTIs represents a potential therapy for patients with HGPS, and hypothesized that retention of the farnesyl group causes progerin to become permanently anchored in the nuclear membrane, disrupting proper nuclear scaffolding and causing the characteristic nuclear blebbing seen in HGPS cells.
A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation.
It is suggested that FTIs could be useful for treating humans with HGPS, as treatment with an FTI increased adipose tissue mass, improved body weight curves, reduced the number of rib fractures, and improved bone mineralization and bone cortical thickness.
Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors
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Prelamin A, Zmpste24, misshapen cell nuclei, and progeria--new evidence suggesting that protein farnesylation could be important for disease pathogenesis.
The posttranslational processing of prelamin A is reviewed, the mutations underlying several human progeroid syndromes are explained, and recent data showing that misshapen nuclei can be ameliorated by treating cells with protein farnesyltransferase inhibitors are summarized.
A Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria
Results suggest that FTIs may have beneficial effects in humans with progeria, and tested the efficacy of an FTI (ABT-100) in Zmpste24-deficient mice, a mouse model of progeria.
Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition.
Exposure to a farnesyltransferase inhibitor (FTI) caused a significant improvement in the nuclear morphology of cells expressing GFP-progerin and in HGPS cells, suggesting that FTIs may represent a therapeutic option for patients with HGPS.
Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype
A genetic cause has now been implicated following the identification of de novo heterozygous mutations in the LMNA gene in the majority of HGPS patients, which is an extremely rare but devastating disorder that mimics premature aging.
Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome.
The results suggest that farnesyl transferase inhibitors represent a possible therapeutic option for individuals with HGPS and/or other laminopathies due to Zmpste24 processing defects.