Sci. Aging Knowl. Environ., 5 October 2005
Vol. 2005, Issue 40, p. nf78
[DOI: 10.1126/sageke.2005.40.nf78]


Turning Back the Clock

Cancer drugs reverse nuclear defects of progeria

R. John Davenport

It could be a fountain of youth--for the already young. A spate of papers published over the last several months reveals that a type of tumor-shrinking drug also corrects flaws in cells of children with progeria, a disease that resembles accelerated aging. However, further tests on animals are necessary before researchers can embark on clinical trials.

Children with Hutchinson-Gilford progeria syndrome (HGPS) appear to age unusually rapidly. They lose hair, their skin wrinkles, and they typically die of cardiovascular disease by their early teens. Their cells divide sluggishly and contain misshapen nuclei. Two years ago, researchers discovered the mutation that triggers this rare disease: a glitch in the gene that encodes lamin A, part of the mesh that supports a cell's nucleus (see "Lamin-tation"). The error removes 50 amino acids from the middle of lamin A, leaving a protein that scientists have dubbed progerin. Normally, a lamin A precursor protein called prelamin A acquires a lipid called a farnesyl group that sends the protein to the nuclear membrane. Then an enzyme called Zmpste24 snips off the end of prelamin A to remove the farnesyl group, producing lamin A (see "Nuclear Fallout"). The HGPS mutation eliminates a segment of the protein that contains the clipping cue, suggesting that the farnesyl group remains attached. In new work, four laboratories examined whether preventing the addition of farnesyl groups to progerin would smooth out the deformed nuclei.

In research reported in August in Human Molecular Genetics, Glynn and Glover verified that progerin is not snipped and retains its farnesyl appendage. Furthermore, they repaired nuclear defects in cells from HGPS patients and cells engineered to produce progerin by treating them with FTIs, anticancer compounds that block farnesyl-adding enzymes. Other groups have made similar observations. Fong and colleagues found that FTIs correct the shape of nuclei in cells from mice that produce progerin and from HGPS patients, they reported online 12 July and 29 August in the Proceedings of the National Academy of Sciences U.S.A. (PNAS). And Leslie Gordon, medical director of the Progeria Research Foundation, and colleagues showed online 29 August in PNAS that farnesyl-resistant progerin doesn't deform nuclei and also confirmed that FTIs repair nuclei.

In the most recent study, cell biologist Susan Michaelis of Johns Hopkins University in Baltimore, Maryland, and colleagues engineered human cells to produce progerin or a form of lamin A with a defective Zmpste24 cutting site. Both types of cells bore lumpy, folded, or otherwise malformed nuclei, similar to those of HGPS cells, they reported online 26 September in PNAS. But when the team added FTIs, most nuclei assumed their regular shape. The treatment also restored normal quantities of a protein that collaborates with lamin A, called Lap2. It dwindles in cells with snarled lamin. This result "broadens the significance" of the FTI work, says Michaelis. "It's not just one feature of the disease that's been reversed."

Together, the papers represent "a major scientific step," says Richard Lee of Harvard University, who studies heart ailments triggered by lamin hang-ups. "It's really quite remarkable" that FTIs mend cellular problems of HGPS and could be a potential treatment for progeria, he adds. However, no one knows whether misshapen nuclei cause disease symptoms, he says. Next, researchers need to show that the drugs improve other aspects of cellular health, such as boosting the ability to divide and restoring normal activity of genes that encode proteins besides Lap2, says developmental biologist Colin Stewart of the National Cancer Institute's Cancer and Developmental Biology Laboratory in Frederick, Maryland. Although previous studies have established that FTIs are safe in children, at least for short treatment periods, scientists will have to test whether the drugs turn back the clock in animals with progerialike symptoms before they try them in humans with HGPS, says Gordon. They'll also need to determine how soon patients should receive the drugs to receive a benefit. But Michaelis says that tissue damage is probably cumulative, so it might never be too late to start treatment, an idea that's bolstered by FTIs' ability to shape up distorted nuclei. At the moment, the findings offer the best chance yet to make children with HGPS young again.

October 5, 2005
  1. B. C. Capell et al., Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proc. Natl. Acad. Sci. U.S.A.., 29 August 2005 [e-pub ahead of print]. doi:10.1073/pnas.0506001102 [Abstract/Free Full Text]
  2. M. W. Glynn and T. W. Glover, Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum. Mol. Genet., 26 August 2005 [e-pub ahead of print]. doi:10.1093/hmg/ddi326 [Abstract/Free Full Text]
  3. M. P. Mallampalli, G. Huyer, P. Bendale, M. H. Gelb, S. Michaelis, Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome. Proc. Natl. Acad. Sci. U.S.A., 26 September 2005 [e-pub ahead of print]. doi:10.1073/pnas.0503712102 [Abstract/Free Full Text]
  4. J. I. Toth et al., Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes. Proc. Natl. Acad. Sci. U.S.A., 29 August 2005 [e-pub ahead of print]. doi:10.1073/pnas.0505767102 [Abstract/Free Full Text]
  5. S. H. Yang et al., Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation. Proc. Natl. Acad. Sci. U.S.A., 12 July 2005 [e-pub ahead of print]. doi:10.1073/pnas.0504641102 [Abstract/Free Full Text]
Citation: R. J. Davenport, Turning Back the Clock. Sci. Aging Knowl. Environ. 2005 (40), nf78 (2005).

Science of Aging Knowledge Environment. ISSN 1539-6150