Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein

Autor: Juan J. Marugan, Maria de Haro, Amanda K Wagner Gee, Lois S. Weisman, Juan Botas, Marc Ferrer, Sai Srinivas Panapakkam Giridharan, Junya Hasegawa, Dimitri Krainc, Wei Zheng, Robin F. Irvine, Hyunkyung Jeong, Ismael Al-Ramahi, Sami J. Barmada, Yu-Chi Chen, Samarjit Patnaik, Nathaniel Safren, Noel Southall, Jonathan H. Clarke, Steve Titus
Přispěvatelé: Patnaik, Samarjit [0000-0002-4265-7620], Hasegawa, Junya [0000-0002-7041-890X], Clarke, Jonathan [0000-0002-4079-5333], Southall, Noel [0000-0003-4500-880X], Marugan, Juan Jose [0000-0002-3951-7061], Apollo - University of Cambridge Repository
Rok vydání: 2017
Předmět:
0301 basic medicine
Retinal degeneration
Huntingtin
Cell
Mutant
Mice
Enzyme Inhibitors
Biology (General)
Cells
Cultured
Neurons
Huntingtin Protein
Gene knockdown
D. melanogaster
Kinase
General Neuroscience
human biology
General Medicine
3. Good health
Cell biology
Phosphotransferases (Alcohol Group Acceptor)
Huntington Disease
medicine.anatomical_structure
Gene Knockdown Techniques
Medicine
Drosophila
Research Article
Human
autophagy
Huntington
QH301-705.5
Science
Biology
Models
Biological
Protein Aggregation
Pathological
lipid kinase
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
medicine
Animals
Humans
Human Biology and Medicine
General Immunology and Microbiology
Autophagy
Fibroblasts
medicine.disease
Disease Models
Animal
030104 developmental biology
Proteolysis
Neuroscience
Zdroj: eLife, Vol 6 (2017)
eLife
ISSN: 2050-084X
Popis: 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.
Databáze: OpenAIRE
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