The Antiaging Protein Klotho Enhances Oligodendrocyte Maturation and Myelination of the CNS

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, Department of Neurology, Boston University School of Medicine and Veterans Administration Boston Healthcare System, Boston, Massachusetts 02130, Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, Massachusetts 02118, Department of Neurology, University of California Los Angeles, Los Angeles, California 90095, Department of Neuroscience, University of Connecticut Medical School, Farmington, Connecticut 06030, and University of Texas Southwestern Medical Center, Dallas, Texas 75390.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 01/2013; 33(5):1927-1939. DOI: 10.1523/JNEUROSCI.2080-12.2013
Source: PubMed


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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    • "Klotho enhances the maturation of the OPCs and myelination of the CNS, a process that is substantial for the regeneration of damaged neurons in MS patients. Moreover, mice knocked-out for the gene encoding Klotho, fail to produce myelin in different parts of the brain (Chen, Sloane, 2013). "
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    ABSTRACT: Recent investigations support that an anti-aging protein, namely Klotho, protects neurons against the oxidative stress and demyelination. We evaluated the protein concentration of Klotho and total anti-oxidant capacity (TAC) in the cerebrospinal fluid (CSF) of patients with relapsing-remitting Multiple Sclerosis (RRMS). Klotho concentration and TAC were significantly lower in patients as compared to controls. Klotho values showed a significant negative correlation with expanded disability status scale (EDSS). Moreover, a significantly positive correlation between TAC levels and Klotho concentrations was detected. Conclusively, Klotho may play an important role in the pathogenesis of MS, at least in part, through the regulation of redox system. Note: The first two authors contributed equally to this work.
    Journal of Neuroimmunology 02/2015; 281. DOI:10.1016/j.jneuroim.2015.02.004 · 2.47 Impact Factor
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    • "Decreased cerebral or cerebellar excitatory amino acid uptake in the brain is expected to cause excitotoxicity [35], [64]. Acccordingly, impaired function of EAAT3 may lead to epilepsy [42]–[46] and hepatic encephalopathy [65]. Moreover, deranged cellular excitatory amino acid uptake by EAAT3 [28], [36]–[41] or EAAT4 [36], [39] may foster the development of schizophrenia. "
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    ABSTRACT: Klotho, a transmembrane protein, which can be cleaved off as β-glucuronidase and hormone, is released in both, kidney and choroid plexus and encountered in blood and cerebrospinal fluid. Klotho deficiency leads to early appearance of age-related disorders and premature death. Klotho may modify transport by inhibiting 1,25(OH)2D3 formation or by directly affecting channel and carrier proteins. The present study explored whether Klotho influences the activity of the Na(+)-coupled excitatory amino acid transporters EAAT3 and EAAT4, which are expressed in kidney (EAAT3), intestine (EAAT3) and brain (EAAT3 and EAAT4). To this end, cRNA encoding EAAT3 or EAAT4 was injected into Xenopus oocytes with and without additional injection of cRNA encoding Klotho. EAAT expressing Xenopus oocytes were further treated with recombinant human β-Klotho protein with or without β-glucuronidase inhibitor D-saccharic acid 1,4-lactone monohydrate (DSAL). Electrogenic excitatory amino acid transport was determined as L-glutamate-induced current (Iglu) in two electrode voltage clamp experiments. EAAT3 and EAAT4 protein abundance in the Xenopus oocyte cell membrane was visualized by confocal microscopy and quantified utilizing chemiluminescence. As a result, coexpression of Klotho cRNA significantly increased Iglu in both, EAAT3 or EAAT4-expressing Xenopus oocytes. Klotho cRNA coexpression significantly increased the maximal current and cell membrane protein abundance of both EAAT3 and EAAT4. The effect of Klotho coexpression on EAAT3 and EAAT4 activity was mimicked by treating EAAT3 or EAAT4-expressing Xenopus oocytes with recombinant human β-Klotho protein. The effects of Klotho coexpression and of treatment with recombinant human β-Klotho protein were both abrogated in the presence of DSAL (10 µM). In conclusion, Klotho is a novel, powerful regulator of the excitatory amino acid transporters EAAT3 and EAAT4.
    PLoS ONE 07/2013; 8(7):e70988. DOI:10.1371/journal.pone.0070988 · 3.23 Impact Factor
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    ABSTRACT: Without the age-regulating protein klotho, mouse lifespan is shortened and the rapid onset of age-related disorders occurs. Conversely, overexpression of klotho extends mouse lifespan. Klotho is most abundant in kidney and expressed in a limited number of other organs, including the brain, where klotho levels are highest in choroid plexus. Reports vary on where klotho is expressed within the brain parenchyma, and no data is available as to whether klotho levels change across postnatal development. We used in situ hybridization to map klotho mRNA expression in the developing and adult rat brain and report moderate, widespread expression across grey matter regions. mRNA expression levels in cortex, hippocampus, caudate putamen, and amygdala decreased during the second week of life and then gradually rose to adult levels by postnatal day 21. Immunohistochemistry revealed a protein expression pattern similar to the mRNA results, with klotho protein expressed widely throughout the brain. Klotho protein co-localized with both the neuronal marker NeuN, as well as, oligodendrocyte marker olig2. These results provide the first anatomical localization of klotho mRNA and protein in rat brain parenchyma and demonstrate that klotho levels vary during early postnatal development.
    Brain research 07/2013; 1527. DOI:10.1016/j.brainres.2013.06.044 · 2.84 Impact Factor
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