期刊
ELIFE
卷 6, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.29123
关键词
-
类别
资金
- Foundation for the National Institutes of Health [R21NS096395]
- Darrel K Royal Research Fund for Alzheimers Disease
- American Heart Association Post Doctoral Fellowship [14POST20480137]
- National Institutes of Health [P30-AG053760, R01-NS097542, R01-N5064015, R01-N5099340]
- University of Michigan Protein Folding Diseases FastForward Initiative
- CHDI Foundation
- Robert A. and Renee E. Belfer Family Foundation
- MRC [MR/J001120/1] Funding Source: UKRI
- Medical Research Council [MR/J001120/1] Funding Source: researchfish
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, PIP4K gamma. Pharmacological inhibition or knock-down of PIP4Ky 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 PIP4Ky 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据