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J. Biol. Chem., Vol. 277, Issue 38, 35503-35508, September 20, 2002
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From the The klotho mouse is an animal model
that prematurely shows phenotypes resembling human aging. Here we
report that in homozygotes for the klotho mutation
(kl
Klotho Protein Deficiency Leads to Overactivation of
µ-Calpain*
,
,,,
Glycobiology and § Biomembrane
Research Groups, Tokyo Metropolitan Institute of Gerontology,
Foundation for Research on Aging and Promotion of Human Welfare, Tokyo
173-0015, Japan, the ¶ Department of Pathology and Tumor Biology,
Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan,
the Division of Biomolecular Characterization, RIKEN
(Institute of Physical and Chemical Research), Saitama 351-0198, Japan, and the ** Core Research for Evolutional Science & Technology (CREST), Saitama 332-0012, Japan
/), 
II-spectrin is highly
cleaved, even before the occurrence of aging symptoms such as
calcification and arteriosclerosis. Because II-spectrin
is susceptible to proteolysis by calpain, we examined the activation of
calpain in kl/ mice. m-Calpain was not
activated, but µ-calpain was activated at an abnormally high level,
and an endogenous inhibitor of calpain, calpastatin, was significantly
decreased. Proteolysis of II-spectrin increased with
decreasing level of Klotho protein. Similar phenomena were observed in
normal aged mice. Our results indicate that the abnormal activation of
calpain due to the decrease of Klotho protein leads to degradation of
cytoskeletal elements such as II-spectrin. Such
deterioration may trigger renal abnormalities in
kl/ mice and aged mice, but Klotho protein
may suppress these processes.
*
This work was supported by Health and Labor Sciences
Research Grants for Comprehensive Research on Aging and Health from the Ministry of Health, Labor and Welfare, Japan (to T. E.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Glycobiology
Research Group, Tokyo Metropolitan Inst. of Gerontology, Foundation for
Research on Aging and Promotion of Human Welfare, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan. Tel.: 81-3-3964-3241 (ext. 3080);
Fax: 81-3-3579-4776; E-mail: endo@tmig.or.jp.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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