How Does Huntingtin Control Synaptic Development?

Duke University, Durham NC

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Abstract

Abstract: Huntington?s Disease (HD) is a fatal, inherited disease caused by an autosomal dominant polyglutamine expansion mutation in the N-terminus of Huntingtin (Htt). HD is characterized by progressive, debilitating motor and psychiatric symptoms, severe neurodegeneration of the striatum and cortex, and premature death. The dominant nature of the Htt mutation has led to the widely-accepted hypothesis that HD is caused by a toxic gain-of-function of mutant Htt protein. However, our laboratory has shown that loss-of-function of Htt due to dominant-negative effects of the Htt mutation also contributes substantially to multiple aspects of HD pathology. Specifically, we have discovered that Htt deletion results in exuberant postnatal synaptogenesis, indicating that Htt is a critical negative regulator of synaptic development. In my graduate studies, I will determine the cellular and molecular mechanisms by which Htt regulates synaptogenesis. Toward this end, my lab has identified that Htt interacts with neuronal pro-synaptogenic receptor a2d-1, and that this interaction is impaired by the HD- causing polyglutamine expansion. Therefore, I hypothesize that the interaction between Htt and a2d-1 is critical for the regulation of synapse development, and that the impairment of this interaction by mutant Htt contributes to synaptic dysfunction observed in mouse models of HD as well as HD patients. I expect that my findings will have a significant impact both through the discovery of important roles of Htt in synaptic development, and by opening new avenues for targets of future HD therapeutics.