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Hutchinson-Gilford progeria syndrome HGPS is caused by the accumulation of a farnesylated form of prelamin A progerin. Hutchinson-Gilford progeria syndrome HGPS is caused by a point mutation in LMNA that alters splicing of the prelamin A transcript and leads to the deletion of 50 amino acids within the carboxyl-terminal portion of prelamin A 12. The amino acid deletion does not alter the molecule’s CaaX motif; consequently, the mutant prelamin A in HGPS commonly called progerin undergoes farnesylation, endoproteolytic trimming of the last three amino acids of the protein, and carboxyl methylation of the newly exposed farnesylcysteine 34.

However, the internal deletion prevents the subsequent cleavage of the carboxyl terminus by ZMPSTE24, the step that would ordinarily release mature lamin A 1 — 3. Because the ZMPSTE24 processing step does not occur, progerin retains a farnesylcysteine methyl ester at its carboxyl terminus.

Progerin is targeted to the nuclear rim 5 — 7interfering with the integrity of the nuclear lamina and causing misshapen cell nuclei 125.

The farnesylation of progerin and the frequency of misshapen nuclei can be reduced by inhibiting protein farnesylation with a protein farnesyltransferase inhibitor FTI 68 — To further explore the concept that protein farnesylation is relevant to the pathogenesis and treatment of disease, Yang et al.

One possibility was that the FTI improved disease phenotypes directly, by interfering with the prenylation of progerin and reducing the intrinsic toxicity of the protein. Another was that the FTIs acted indirectly, by interfering with the processing of other farnesylated proteins in cells aside from progerin. An indirect effect was not farfetched in our opinion. The concept that FTIs could act in an unanticipated fashion is not novel.

FTIs were developed to inhibit cancer cell growth by blocking the farnesylation of the Ras proteins 16but it is now widely assumed that the anticancer effects of these drugs are mediated mainly by their effects on other proteins in cells Mice were fed a chow diet and housed in a virus-free barrier facility with a 12 h light-dark cycle.

ABT was mixed in drinking water containing 0. Vehicle-treated mice were given drinking water with 0. The FTI was initiated at 4 weeks of age and was continued for up to 38 weeks of age at that time point, any mouse that had not yet succumbed to the disease was euthanized. Plasma FTI levels were measured as described 12 — Body weights were assessed weekly, and body weight curves were compared with repeated-measures ANOVA and the log rank test.

The number of surviving mice was recorded weekly and expressed as a percentage of the total number of mice. Differences in survival curves were assessed by the Kaplan-Meier method. Body fat depots reproductive, inguinal, and mesenteric were measured when each mouse died or was euthanized. Differences were assessed with a two-tailed Student’s t -test.


After opening the thoracic cavity and removing the heart and lungs, the interior of the thorax was photographed and rib fractures were counted 12 Mean bone density and bone cortical thickness in the ribs were measured with computer-assisted tomographic scans. Procedures for preparing liver extracts and Western blotting techniques have been described previously 1214 To detect lamins A and C and progerin, we used a 1: Antibody binding was detected with an Odyssey infrared scanner Li-Cor.

To detect prelamin A, we bbauch a 1: To detect HDJ-2, we used a 1: AG is incorporated by cells into AG pyrophosphate, a farnesyldiphosphate analog, which is used by protein farnesyltransferase as a substrate to farnesylate CaaX proteins. AG incorporation into cellular proteins was detected by western blotting with a mouse monoclonal antibody specific for AG, diluted 1: The plasma levels of ABT in treated mice were similar to those in earlier studies 12 — 14ranging from 0.

Interestingly, there were lower levels of mature spielmanms A, relative to actin, in liver extracts from FTI-treated mice Fig. For these studies, we used the same concentration of ABT that we achieved in the plasma of mice 0. The bauhc mobility of progerin, lamin B1, and lamin B2 are virtually identical, and all are farnesylated; hence, the antibody against AG detected a farnesylated protein in both cell lines in the absence of an FTI. Treatment with an FTI lowers steady-state levels of mature lamin A.

Western blots were also performed with antibodies against HDJ-2, another farnesylated protein.

Actin was used as a loading control. Error bars indicate SEM. Long-term treatment of fibroblasts with ABT lowers steady-state levels of mature lamin A, relative to lamin C or actin. Consistent with earlier studies by Yang et al. Body weights were measured weekly. We assessed the impact of the FTI treatment on spontaneous rib fractures in both male and female mice.

All mice that survived to 38 weeks of age were euthanized at that time point. During the past few years, Yang et al. Instead, we wondered whether the effect of the FTI might be more indirect, perhaps secondary to inhibiting the farnesylation of other cellular proteins.

This prediction was not borne out. We suspect bxuch the trend simply reflected the play of chance. However, if one were forced to suggest a potential explanation for the trend, one could point to the lower levels of mature lamin A in the setting of FTI treatment. Genetic studies have suggested that lower levels of lamin Dder synthesis reduce the disease phenotypes elicited by a Lmna HG allele The finding of lower lamin A levels in association with FTI treatment was also observed in earlier studies 814 The mechanism for the fall in lamin A levels is unclear but we suspect that sustained blockade of prelamin A farnesylation leads to the eventual spielmznns of nonfarnesylated prelamin A, spielmanjs the production of mature lamin A.


Indeed, questions were raised about whether an FTI is the most baucg drug for inhibiting the prenylation of progerin David Frost and Ms. Joy Bauch Abbott Laboratories for their advice and technical expertise.

Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. National Center for Biotechnology InformationU. Journal List J Lipid Ded v. Author information Article notes Copyright and License information Disclaimer.

Received Oct 20; Revised Oct Author’s Choice – Final version full access. This article has been cited by other articles in PMC. Analysis of disease phenotypes Body spielmannns were assessed weekly, and body weight curves were compared with repeated-measures ANOVA and the log rank test.

Western blots and metabolic labeling studies Procedures for preparing liver extracts and Western blotting techniques have been described previously 1214 Open in a separate window. Recurrent de novo point mutations in lamin A cause Hutchinson—Gilford progeria syndrome. Lamin A truncation in Hutchinson—Gilford progeria. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria—new evidence suggesting that protein farnesylation could be important for disease pathogenesis.

Der Bauch des Spielmanns

Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation.

Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes. Inhibiting farnesylation reverses the nuclear morphology baych in a HeLa cell model for Hutchinson-Gilford progeria syndrome. Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome.

Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Treatment with a protein farnesyltransferase inhibitor improves disease phenotypes in mice with a targeted Hutchinson-Gilford progeria spielmanhs mutation. A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Treatment with a farnesyltransferase inhibitor improves survival in mice with a Hutchinson-Gilford progeria syndrome mutation.

Progerin elicits disease phenotypes of progeria in mice whether or not it is farnesylated. Protein farnesyltransferase inhibitors block the bauxh of ras -dependent tumors in nude mice. Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: Antitumor activity of orally bioavailable farnesyltransferase inhibitor, ABT, is mediated by antiproliferative, proapoptotic, and antiangiogenic effects in xenograft models.

Team | Max Planck Institute for Molecular Genetics

Rer to analyze protein farnesylation in cells. Eliminating the synthesis of mature lamin a reduces disease phenotypes in mice carrying a Hutchinson-Gilford progeria syndrome allele.

Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Support Center Support Center. Please review our privacy policy.