Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein
- Baylor College of Medicine, United States
- University of Michigan, United States
- National Institutes of Health, United States
- Northwestern University, United States
- University of Cambridge, United Kingdom
Abstract
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.
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Author details
Funding
National Institutes of Health (R01-NS064015)
- Lois S Weisman
National Institutes of Health (R01-NS099340)
- Lois S Weisman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All vertebrate animal work was approved by the Institutional Animal Use & Care Committee at the University of Michigan (PRO00007096).
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein
eLife 6:e29123.
https://doi.org/10.7554/eLife.29123
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