Huntington's disease (HD) is an autosomal-dominant, progressive neurodegenerative disorder featuring devastating clinical symptoms that include motor deficits, cognitive decline, and behavioral impairments. To date, most research efforts towards the development of therapeutic strategies in HD have been largely focused on inhibition of pathways leading to the loss of neuronal somata, failing to address or even consider the progressive loss of neuritic connectivity that takes place much earlier in the disease process. Building on a solid body of published findings and strong preliminary data, this application aims to illuminate specific therapeutic targets and mechanisms underlying axonal pathology in HD. Experiments proposed under Aim 1 will directly evaluate the contribution of JNK3, a potentially druggable protein kinase, to the axonal pathology induced by mutant huntingtin (mhtt) expression in vivo. Extending these studies, experiments under Aim 2 will identify JNK3-dependent alterations in the phosphorylation of axonal proteins induced by mhtt. Together, these studies will help illuminate a molecular basis linking JNK3 activation to mhtt-induced axonal degeneration.
Mutations leading to expansion of a polyglutamine tract in the protein huntingtin represent the primary cause of Huntington's disease (HD), a devastating neurodegenerative disorder affecting over 30,000 symptomatic Americans, with 200,000 or more at risk of inheriting the disease. Despite many years of research, no effective therapies for HD have been developed to prevent disease progression. To date, most research efforts and funding resources have been directed to the identification of mechanisms linking neuronal cell death in HD. However, cumulative pathological, electrophysiological, and behavioral evidence revealed deficits in neuronal connectivity that occurs much earlier in the course of disease. Providing a cellular basis for these deficits, our recent studies using YFP-R6/2 reporter mice provided direct evidence that neurons affected in HD follow a dying back pattern of degeneration. A major implication of these findings is that any effective therapeutic strategies to treat HD should aim to prevent or halt the progressive loss of axonal connectivity that takes place very early in the disease process. However, the axonal compartment has received little attention in the context of HD. Consequently, our knowledge of molecular mechanisms underlying axonal and neuritic pathology in HD remains meager. It is well established that mutant huntingtin (mhtt) promotes deficits in axonal transport, a cellular process critical for the appropriate maintenance of axons. Further, studies by our group revealed that this toxic effect of mhtt is mediated by the protein kinase JNK3, which was also found to phosphorylate the major motor protein kinesin-1. The relevance of these findings to HD is highlighted by preliminary in vivo studies in this proposal documenting a remarkable beneficial effect of genetic JNK3 deletion on R6/2 mice neuropathology and survival. Based on these precedents, studies proposed in this application will directly evaluate the contribution of JNK3 to axonal degeneration in vivo, and identify JNK3-dependent alterations in the phosphorylation of axonal proteins associated with mhtt expression. Overall, findings from these studies will help establish whether inhibition of JNK3 helps preserve neuronal connectivity in HD, and provide a molecular basis linking JNK3 activation to mtt-induced neuritic pathology.
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