Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein

Ismael Al-Ramahi, Sai Srinivas Panapakkam Giridharan, Yu-Chi Chen, Samarjit Patnaik, Nathaniel Safren, Junya Hasegawa, Maria de Haro, Amanda K Wagner Gee, Steven A Titus, Hyunkyung Jeong, Jonathan Clarke, Dimitri Krainc, Wei Zheng, Robin F Irvine, Sami Barmada, Marc Ferrer, Noel Southall, Lois S Weisman, Juan Botas, Juan Jose Marugan

The discovery of the causative gene for Huntington's disease (HD) has promoted numerous efforts to uncover cellular pathways that lower levels of mutant huntingtin protein (mHtt) and potentially forestall the appearance of HD-related neurological defects. Using a cell-based model of pathogenic huntingtin expression, we identified a class of compounds that protect cells through selective inhibition of a lipid kinase, PIP4Kγ. Pharmacological inhibition or knock-down of PIP4Kγ modulates the equilibrium between phosphatidylinositide (PI) species within the cell and increases basal autophagy, reducing the total amount of mHtt protein in human patient fibroblasts and aggregates in neurons. In two Drosophila models of Huntington's disease, genetic knockdown of PIP4K ameliorated neuronal dysfunction and degeneration as assessed using motor performance and retinal degeneration assays respectively. Together, these results suggest that PIP4Kγ is a druggable target whose inhibition enhances productive autophagy and mHtt proteolysis, revealing a useful pharmacological point of intervention for the treatment of Huntington's disease, and potentially for other neurodegenerative disorders.