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 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.
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Ci-Di
CD
Chen
Jacob A
JA
Sloane
Hu
H
Li
Nurgul
N
Aytan
Eustathia L
EL
Giannaris
Ella
E
Zeldich
Jason D
JD
Hinman
Alpaslan
A
Dedeoglu
Douglas L
DL
Rosene
Rashmi
R
Bansal
Jennifer I
JI
Luebke
Makoto
M
Kuro-o
Carmela R
CR
Abraham
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002452:Cell Count; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003337:Corpus Callosum / Q000378:metabolism; D005260:Female; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D000090265:Klotho Proteins; D051379:Mice; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism*; D009900:Optic Nerve / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050794:STAT1 Transcription Factor / Q000502:physiology
D004676:Myelin Basic Protein; D050794:STAT1 Transcription Factor; D005966:Glucuronidase; D000090265:Klotho Proteins