The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS
We have previously shown that myelin abnormalities characterize the normal aging process of the brain and that an age-associated reduction in Klotho is conserved across species. Predominantly generated in brain and kidney, Klotho overexpression extends life span, whereas loss of Klotho accelerates t...
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Published in | The Journal of neuroscience Vol. 33; no. 5; pp. 1927 - 1939 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Society for Neuroscience
30.01.2013
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Subjects | |
Online Access | Get full text |
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Summary: | We have previously shown that myelin abnormalities characterize the normal aging process of the brain and that an age-associated reduction in Klotho is conserved across species. Predominantly generated in brain and kidney, Klotho overexpression extends life span, whereas loss of Klotho accelerates the development of aging-like phenotypes. Although the function of Klotho in brain is unknown, loss of Klotho expression leads to cognitive deficits. We found significant effects of Klotho on oligodendrocyte functions, including induced maturation of rat primary oligodendrocytic progenitor cells (OPCs) in vitro and myelination. Phosphoprotein analysis indicated that Klotho's downstream effects involve Akt and ERK signal pathways. Klotho increased OPC maturation, and inhibition of Akt or ERK function blocked this effect on OPCs. In vivo studies of Klotho knock-out mice and control littermates revealed that knock-out mice have a significant reduction in major myelin protein and gene expression. By immunohistochemistry, the number of total and mature oligodendrocytes was significantly lower in Klotho knock-out mice. Strikingly, at the ultrastructural level, Klotho knock-out mice exhibited significantly impaired myelination of the optic nerve and corpus callosum. These mice also displayed severe abnormalities at the nodes of Ranvier. To decipher the mechanisms by which Klotho affects oligodendrocytes, we used luciferase pathway reporters to identify the transcription factors involved. Together, these studies provide novel evidence for Klotho as a key player in myelin biology, which may thus be a useful therapeutic target in efforts to protect brain myelin against age-dependent changes and promote repair in multiple sclerosis. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 J.A.S., H.L., N.A., and E.L.G. contributed equally to this work. Author contributions: C.-D.C., J.A.S., R.B., and C.R.A. designed research; C.-D.C., J.A.S., N.A., E.L.G., E.Z., J.D.H., and J.I.L. performed research; A.D. and M.K-o. contributed unpublished reagents/analytic tools; C.-D.C., J.A.S., H.L., N.A., E.L.G., J.D.H., and C.R.A. analyzed data; C.-D.C., J.A.S., J.D.H., D.L.R., J.I.L., and C.R.A. wrote the paper. |
ISSN: | 0270-6474 1529-2401 1529-2401 |
DOI: | 10.1523/JNEUROSCI.2080-12.2013 |