Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in exon 1 of the Huntingtin (HTT) gene. There are no effective treatments for this fatal disease. Thus, identification of new target pathways to mitigate Huntington's disease is critical. We discovered two targets that lower mutant HTT protein (mHTT) and thus hold potential for disease-modifying therapy. In an unbiased, high-throughput screen, we discovered PIP4Kγ-INH, an allosteric inhibitor of PIP4Kγ. Treatment of HdhQ111 knock-in mouse striatal neurons with PIP4Kγ-INH, reduced the levels of HTTQ111. Moreover, exposure of Huntington patient fibroblasts to inhibition or knock-down of PIP4Kγ, reduced mutant huntingtin protein. PIP4Kγ converts PI5P to PI(4,5)P2. We determined which phosphoinositide lipids are impacted by PIP4Kγ-INH, and identified an orthogonal approach to induce similar changes in these lipids. Notably this new approach might also lower mutant HTT aggregates. Indeed, co-expression of huntingtin exon1-polyQ74-GFP (httQ74-GFP) combined with activation of a lipid kinase reduced httQ74 aggregates by >35%. Thus, orthogonal approaches that change phosphoinositide lipids have the potential to lower HD levels. The overall goal of this proposal is to determine whether inhibition of PIP4Kγ and/or activation of a lipid kinase should be test for the potential to ameliorate phenotypes associated with HD. This goal will be pursued with the following aims: 1) Determine the effects of activation of a specific lipid kinase on cellular levels of mutant HTT. 2) Determine mechanisms whereby inhibition of PIP4Kγ or activation of a specific lipid kinase lowers mutant HTT. 3) Determine whether inhibition of PIP4Kγ and/or activation of a specific lipid kinase mitigates disease pathogenesis in animal models of HD. We predict that the outcomes of these studies will reveal that one or both lipid kinase targets are attractive options for further testing as possible disease-modifying agents in preclinical studies.