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Elife. 2017 Dec 26;6. pii: e29123. doi: 10.7554/eLife.29123.

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

Author information

1
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.
2
Baylor College of Medicine, Texas Medical Center, Houston, United States.
3
Department of Cell and Developmental Biology, Life Sciences Institute, University of Michigan, Ann Arbor, United States.
4
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Rockville, United States.
5
Department of Neurology, University of Michigan, Ann Arbor, United States.
6
The Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
7
Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom.
#
Contributed equally

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.

KEYWORDS:

D. melanogaster; Huntington; autophagy; human; human biology; lipid kinase; medicine; neuroscience

PMID:
29256861
PMCID:
PMC5743427
DOI:
10.7554/eLife.29123
[Indexed for MEDLINE]
Free PMC Article

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