Huntingtin links inflammasome pathway in Huntington's disease Pathogenesis

Abstract Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene, leading to the pathogenic expansion of a polyglutamine tract in the huntingtin protein. The key pathological features include striatal medium spiny neuronal loss, and the presence of cellular inclusion bodies containing mutant HTT proteins. There is no disease-modifying treatment for HD. The recent failure of the clinical trial of HTT reduction approaches indicates the urgent need for development of novel therapeutic modalities. Neuroinflammation has implications in HD pathogenesis. HD human tissue and mouse models demonstrate activated microglia and astrocytes and elevated levels of plasma cytokines and chemokines, all potentially contributing to HD pathology. Inflammasomes are key components of the innate immune response, whose formation is triggered by substances produced through infections, tissue damage, or other disorders. Inflammasome activation has implications in neuroinflammation and neurodegeneration. Our pilot studies found that HTT interacts with NLRP3 and activates NLRP3-inflammasome, and that knockdown of NLRP3 protects against mHTT-induced neurodegeneration in cultured human striatal neurons. These results suggest that HTT/NLRP3-linked inflammasome pathways may play a critical role in HD pathogenesis. Thus, we propose to test the hypothesis that mutant HTT interacts with and activates the NLRP3-inflammasome in neurons, thereby resulting in neurodegeneration and HD pathology, and thus that NLRP3 could be a therapeutic target via 3 aims. Aim 1. We will characterize the interaction of HTT and NLRP3. Aim 2. We will assess whether mutant HTT activates the NLRP3-inflammasome in neurons, leading to neurodegeneration. Aim 3. We will evaluate whether downregulation of the HTT/NLRP3-inflammasome pathway as a novel treatment strategy in HD mouse models. These studies will elucidate the roles of mHTT and NLRP3 interactions in activation of the inflammasome pathway and determine how this contributes to the neurodegeneration underlying HD pathogenesis. Our results may provide novel drug targets and therapeutic strategies for future HD interventions, and may also implicate a shared mechanism of inflammasome activation for other neuroinflammation-related neurological disorders.