REGULATION OF AXONAL DEGENERATION BY THE DLK KINASE

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 DESCRIPTION (provided by applicant): Neuronal injury and disease are a huge burden to patients, families, and society. Improved treatments for neurological disorders will require a better understanding of how neurons respond to pathological insults in order to manipulate these responses for therapeutic benefit. Axons are a particularly vulnerable component of neural circuits that are damaged in many neurological diseases. With injury or disease, there are three primary neuronal responses to axon injury: 1) the axon may undergo a regulated self-destruction mechanism of axonal degeneration, 2) in the peripheral nervous system the neuron may activate an axonal growth program that can result in axonal regeneration, and 3) the injured neuron may die. The MAP3K Dual leucine zipper kinase (DLK) is a key regulator of each neuronal response to injury, axon degeneration, axon regeneration, and neuronal cell death. The central role of DLK in the neuronal response to injury leads to the hypothesis that DLK is a key sensor of axonal injury, transducing that signal to the remainder of the cell where it may trigger degenerative, regenerative, and apoptotic responses. While it is clear that DLK plays a seminal role in the axonal injury response pathway, numerous open questions remain that must be addressed in order to define the therapeutic potential of targeting DLK. First, how does DLK promote both regenerative and degenerative responses to injury? Understanding these mechanisms could be useful for selectively manipulating these outcomes. Second, while DLK is necessary for induction of the regenerative program following axon injury, it is not known whether activation of DLK is sufficient to activate this program in the absence of injury, or to enhance the regenerative capacity following injury. Improvements to regeneration in the PNS would have important clinical consequences, since the slow pace of endogenous regeneration is the key obstacle to functional recovery. Finally, what mechanisms regulate DLK signaling? Identification of proteins that modulate DLK- dependent signaling will generate novel therapeutic targets for the diseased or injured nervous system. If successful, this work will significantly advance our understanding of the function, regulation, and therapeutic potential of the DLK pathway.