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

Published version
Peer-reviewed

Type

Article

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Authors

Al-Ramahi, Ismael 
Giridharan, Sai Srinivas Panapakkam 
Chen, Yu-Chi 
Safren, Nathaniel 

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.

Description

Keywords

D. melanogaster, Huntington, autophagy, human, human biology, lipid kinase, medicine, neuroscience, Animals, Autophagy, Cells, Cultured, Disease Models, Animal, Drosophila, Enzyme Inhibitors, Fibroblasts, Gene Knockdown Techniques, Humans, Huntingtin Protein, Huntington Disease, Mice, Models, Biological, Neurons, Phosphotransferases (Alcohol Group Acceptor), Protein Aggregation, Pathological, Proteolysis

Journal Title

Elife

Conference Name

Journal ISSN

2050-084X
2050-084X

Volume Title

6

Publisher

eLife Sciences Publications, Ltd
Sponsorship
Medical Research Council (MR/J001120/1)