The prohibitin family and their function in myelination and axonal health

抽象的。 髓鞘是神经冲动传导和保护轴突所必需的。受损的 髓鞘的形成或破坏会导致一系列衰弱的疾病。的疾病 外周髓鞘是最常见的神经肌肉疾病和原因之一 严重残疾。外周髓鞘的基本机制是- 形成雪旺细胞的分化和髓鞘形成，它们如何维持健康的髓鞘 鞘以及它们是如何支持轴突的，人们只了解了一部分。使用创新的 研究细胞间相互作用的系统我们最近发现了一个新的分子家族，即 抑制素是体内雪旺细胞与轴突、髓鞘和细胞相互作用所必需的 保持健康的髓鞘和轴突。小鼠雪旺细胞中抑制素的缺失导致 DYS-髓鞘形成、脱髓鞘和轴突变性。Prohibitins是保守的 存在于线粒体、质膜和细胞核中的跨膜蛋白。他们 起信号适配器和伴侣的作用，它们参与黏附、信号转导、 和衰老。我们建议使用最先进的和创新的组合 体内和体外技术检验雪旺细胞中的禁止素-2是 质膜信号复合体的一部分，在发育早期与轴突相互作用， 而线粒体中的禁止素-1/禁止素-2复合体则维持髓鞘和轴突 正直。我们将确定禁忌素的相互作用，并发现禁忌素是如何调节的 雪旺细胞的衰老、蛋白稳定和线粒体功能。这些数据很可能 明确抑制素在髓鞘形成和轴突保护中的新功能，并可能揭示 外周轴突-神经胶质细胞相互作用的新分子机制 神经病。

Abstract. Myelin is required for conduction of nerve impulses and to protect axons. Impaired formation or destruction of myelin causes a series of debilitating diseases. Diseases of peripheral myelin are among the most common neuromuscular disorders and cause significant disability. The fundamental mechanisms that underlie how peripheral myelin- forming Schwann cells differentiate and myelinate, how they maintain a healthy myelin sheath and how they support axons are only partially understood. Using an innovative system to study cell-cell interactions we recently identified a new family of molecules, the prohibitins, which are required in Schwann cells in vivo to interact with axons, myelinate and maintain healthy myelin and axons. Deletion of prohibitins in Schwann cells in mice causes dys-myelination, de-myelination and axonal degeneration. Prohibitins are conserved transmembrane proteins found in mitochondria, plasmamembranes and nuclei. They function as signaling adaptors and chaperones and they are involved in adhesion, signaling, and senescence. We propose to use a combination of state-of-the art and innovative techniques in vivo and in vitro to test the hypotheses that prohibitin-2 in Schwann cells is part of a plasma membrane signaling complex that interact with axons early in development, while a prohibitin-1/prohibitin-2 complex in the mitochondria maintains myelin and axon integrity. We will identify prohibitins interactors and discover how prohibitins regulate senescence, proteostasis and mitochondria function in Schwann cells. These data are likely to define the novel function of prohibitins in myelination and axon protection, and may reveal new molecular mechanisms that are important for axo-glial interactions during peripheral neuropathies.