Subcellular and molecular machinery underlying de novo protein synthesis in regenerating axons

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Peripheral nerve injury (trauma, neuropathic disorders) in humans is common and often debilitating. While peripheral nerves do regenerate better than that of central nervous system, recovery is often incomplete, misdirected or associated with incapacitating neuropathic pain. Despite extensive efforts aimed at defining the nature of an injury response, the precise cellular and molecular mechanisms remain however, poorly defined. Thus, one of the main objectives of this proposal is to define the cellular and molecular mechanisms underlying an injury response, and those that promote nerve regeneration in a rodent model of nerve injury. Central to all regenerative responses is the protein synthetic machinery, which is required not only to inform the nucleus that an injury has occurred but also to synthesize proteins that are essential for new growth and regeneration - a number of which are synthesized locally in the axonal compartment. Based on our preliminary results (where we showed that a bona vide rough endoplasmic reticulum and Golgi apparatus are absent in axons), we hypothesize that axons synthesize proteins through a mechanism that is distinct from that of somal protein synthesis. We seek to determine whether all translational components needed for co-translational targeting of proteins into the ER are indeed: a) present in axons, b) how they are organized at the subcellular level, and c) how they direct local protein synthesis. Secondly, we will determine whether these elements of the proteins synthetic machinery increase in injured and regenerating axons and then determine their cellular origin. In view of our recent data, in which we demonstrated that glia cells can "export" polyribosomes to injured axons, we anticipate an unexpected new role for glia cells in directing protein synthesis in axons. Taken together, these results will shed new light on fundamental mechanisms by which axons respond to injury signals, and in the future may pave the way for novel treatment strategies to promote nerve repair after trauma.