Huntington?s disease (HD) is one of nine incurable neurodegenerative disorders caused by pathogenic polyglutamine (polyQ) expansions. Although each polyQ neurodegenerative disease develops via distinct genetic, molecular and cellular mechanisms, a feature common to all of them is transcriptional dysregulation. PolyQ-expanded proteins interact abnormally with transcriptional factors and disrupt transcription leading to neurotoxicity. Thus, normalizing transcription is a therapeutic strategy for HD and for polyQ disorders in general. A novel neuronal nuclear pathway, the sphingosine kinase 2 (SK2) pathway, regulates transcription by modulating transcription factors. In our recent paper, we demonstrated that overexpressed SK2 is toxic to neurons. We discovered that SK2 is hyperphosphorylated in brain samples from a mouse model of HD, the BACHD mice, indicating its increased activity. In our preliminary data, we also discovered a potential new binding partner of SK2 ? ZHX2, zinc fingers and homeoboxes 2 transcriptional repressor. The ectopic expression of ZHX2 in primary neurons is also toxic. Remarkably, ZHX2 levels are increased in brain samples from the BACHD mice. We hypothesize that SK2/ZHX2 is a component of the pathogenic mechanisms in HD and that inhibiting SK2/ZHX2 signaling will promote survival of HD neurons. In the first aim, we will characterize the SK2/ZHX2 pathway in primary neurons. In the second aim, we will define the role of SK2/ZHX2 in HD. We recently demonstrated that an inhibitor of SK2 improves neuronal survival in two rodent neuron models of HD. Therefore, in the third aim, we will determine if inhibiting or downregulating SK2 alleviates disease phenotypes in HD mice. These studies could form the basis for SK2/ZHX2 pathway?based drug discovery, with applications to the polyQ disorders.
Neurotoxicity occurs in Huntington?s disease and other polyglutamine disorders. Normalizing neuronal health has been suggested as a therapeutic strategy. This project investigates the role of a novel neuronal nuclear pathway, the sphingosine kinase 2 and zinc fingers and homeoboxes 2 pathway, in neuronal toxicity in wild-type neurons and in neurons that express mutant huntingtin, the protein that causes Huntington's disease.
