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Publication

Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein.

eLife | 2017

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.

Pubmed ID: 29256861 RIS Download

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Associated grants

Agency: NIA NIH HHS, United States
Id: P30 AG053760
Agency: NINDS NIH HHS, United States
Id: R01 NS097542
Agency: NINDS NIH HHS, United States
Id: R21 NS096395
Agency: Medical Research Council, United Kingdom
Id: MR/J001120/1
Agency: NINDS NIH HHS, United States
Id: R01 NS064015
Agency: NINDS NIH HHS, United States
Id: R01 NS099340

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