Sci. Aging Knowl. Environ., 18 September 2002
Mice lacking a nucleus-bracing protein appear to age quickly
Key Words: CAAX endoprotease Ste24 metalloproteinase
Abstract: When nuclei sag, the bodies containing them might not be far behind. Mice without an enzyme that helps bolster the nucleus appear to age prematurely. They acquire brittle bones and weak muscles, heal slowly, and lose hair. It's unclear whether these defects and aging share the same mechanism, but the model might reveal clues about how bones and muscles degrade.
A protein called lamin A structurally reinforces the membrane surrounding a cell's nucleus. Defects in the lamin A gene cause several illnesses, including muscular dystrophies and some types of heart disease. A particular lamin A mutation results in a rare human disease called mandibuloacral dysplasia--characterized by brittle bones, short stature, and loss of hair--that some researchers consider a premature aging disease (see Further Reading and "Of Hyperaging and Methuselah Genes"). A mammalian enzyme called Zmpste24 produces mature lamin A by trimming a precursor protein, prelamin A.
To better understand how Zmpste24 functions in an organism, Bergo and colleagues deleted one or both copies of Zmpste24 in mice. Animals with one copy appeared normal for the first year of life, but at around 15 months they began to lose weight, muscle strength, and hair; in contrast, normal 15-month-old rodents were vigorous, healthy, and plush. Mice missing both copies of the gene deteriorated even sooner; they were small, weak, and going bald at 8 weeks, and they died at 6 or 7 months. These more severely affected animals also suffered from spontaneous bone fractures that resisted healing. Furthermore, they displayed some aspects of osteoporosis, such as low bone density.
Examining slices of bone from the mice, the team found unusually high numbers of dying or dead osteoblasts, a type of cell that builds bone, but robust numbers of osteoclasts, cells that break down bone (see "SHIPping Out Bone Breakers"). This observation suggests that a dearth of Zmpste24 upsets the balance between bone formation and destruction, similar to what occurs in age-related bone loss. Other features of the gene deficiency, such as weight loss, might result from malnutrition rather than premature aging, because the animals ate less, apparently due to the fragility of their jawbones.
It's too early to tell whether the Zmpste24-deficient mice will illuminate aging-related processes, says gerontologist George Martin of the University of Washington, Seattle, but the animals deserve further attention. The mice that lack only one gene copy are "exactly the kind of model [that] researchers who study aging are interested in, " he says: They start out healthy and age fast. The idea of a link between lamin A and aging is new. "The effect of lamins in the aging process hasn't been looked at," says developmental biologist Colin Stewart of the National Cancer Institute in Bethesda, Maryland. Lamin biology has been a "piddling little backwater" but is beginning to demand attention because of the recent findings that place lamins at the center of many diseases, he says. In addition to maintaining our muscles and hearts, the new work hints that Zmpste24 might preserve other aspects of our structural integrity as we age.
M. O. Bergo, B. Gavino, J. Ross, W. K. Schmidt, C. Hong, L. V. Kendall, A. Mohr, M. Meta, H. Genant, Y. Jiang, E. R. Wisner, N. van Bruggen, R. A. D. Carano, S. Michaelis, S. M. Griffey, S. G. Young, Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect. Proc. Natl. Acad. Sci. U.S.A., 16 September 2002 [e-pub ahead of print]. [Abstract] [Full Text]
G. Novelli, A. Muchir, F. Sangiuolo, A. Helbling-Leclerc, M. R. D'Apice, C. Massart, F. Capon, P. Sbraccia, M. Federici, R. Lauro, C. Tudisco, R. Pallotta, G. Scarano, B. Dallapiccola, L. Merlini, G. Bonne, Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am. J. Hum. Genet. 71, 426-431 (2002). [Abstract] [Full Text]
Citation: M. Beckman, Nuclear Fallout. Science's SAGE KE (18 September 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/37/nw129
Science of Aging Knowledge Environment. ISSN 1539-6150