학술논문
Inhibition of PIP4Kg ameliorates the pathological effects of mutant huntingtin protein.
Document Type
Article
Author
Al-Ramahi, Ismael; Giridharan, Sai Srinivas Panapakkam; Yu-Chi Chen; Patnaik, Samarjit; Safren, Nathaniel; Hasegawa, Junya; de Haro, Maria; Gee, Amanda K. Wagner; Titus, Steven A.; Hyunkyung Jeong; Clarke, Jonathan; Krainc, Dimitri; Wei Zheng; Irvine, Robin F.; Barmada, Sami; Ferrer, Marc; Southall, Noel; Weisman, Lois S.; Botas, Juan; Marugan, Juan Jose
Source
Subject
*HUNTINGTON disease
*HUNTINGTIN protein
*PROTEIN expression
*FIBROBLASTS
*RETINAL degeneration
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Language
ISSN
2050-084X
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, PIP4Kg. Pharmacological inhibition or knock-down of PIP4Kg 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 PIP4Kg 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. [ABSTRACT FROM AUTHOR]