The prohibitin family and their function in myelination and axonal health

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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.