Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
J Neurosci. 2013 Jan 30;33(5):1927-39. doi: 10.1523/JNEUROSCI.2080-12.2013.
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.
我们之前已经表明，髓鞘异常是大脑正常老化过程的特征，并且 Klotho 随年龄的减少在物种间是保守的。Klotho 主要在大脑和肾脏中产生，其过表达可延长寿命，而 Klotho 的缺失则加速了衰老表型的发展。虽然 Klotho 在大脑中的功能尚不清楚，但 Klotho 表达的缺失会导致认知缺陷。我们发现 Klotho 对少突胶质细胞功能有显著影响，包括体外诱导大鼠原代少突胶质前体细胞（OPC）成熟和髓鞘形成。磷酸蛋白分析表明，Klotho 的下游效应涉及 Akt 和 ERK 信号通路。Klotho 增加 OPC 的成熟，而 Akt 或 ERK 功能的抑制会阻断对 OPC 的这种作用。Klotho 敲除小鼠和对照同窝仔鼠的体内研究表明，敲除小鼠的主要髓鞘蛋白和基因表达显著减少。通过免疫组织化学，Klotho 敲除小鼠的总和成熟少突胶质细胞数量明显减少。引人注目的是，在超微结构水平上，Klotho 敲除小鼠的视神经和胼胝体的髓鞘形成明显受损。这些小鼠在Ranvier 结处也表现出严重的异常。为了解 Klotho 影响少突胶质细胞的机制，我们使用荧光素酶途径报告基因来鉴定涉及的转录因子。综上所述，这些研究为 Klotho 作为髓鞘生物学中的关键因子提供了新的证据，这可能使其成为保护大脑髓鞘免受年龄相关变化和促进多发性硬化症修复的有价值的治疗靶点。
