Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein

Ismael Al-Ramahi; Sai Srinivas Panapakkam Giridharan; Yu Chi Chen; Samarjit Patnaik; Nathaniel Safren; Junya Hasegawa; Maria de Haro; Amanda K.Wagner Gee; Steven A. Titus; Hyunkyung Jeong; Jonathan Clarke; Dimitri Krainc; Wei Zheng; Robin F. Irvine; Sami Barmada; Marc Ferrer; Noel Southall; Lois S. Weisman; Juan Botas; Juan Jose Marugan

doi:10.7554/eLife.29123

Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein

Ismael Al-Ramahi, Sai Srinivas Panapakkam Giridharan, Yu Chi Chen, Samarjit Patnaik, Nathaniel Safren, Junya Hasegawa, Maria de Haro, Amanda K.Wagner Gee, Steven A. Titus, Hyunkyung Jeong, Jonathan Clarke, Dimitri Krainc, Wei Zheng, Robin F. Irvine, Sami Barmada, Marc Ferrer, Noel Southall, Lois S. Weisman, Juan Botas^*, Juan Jose Marugan

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

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 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.

Original language	English (US)
Article number	e29123
Journal	eLife
Volume	6
DOIs	https://doi.org/10.7554/eLife.29123
State	Published - Dec 26 2017

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)
Neuroscience(all)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.29123

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Al-Ramahi, I., Giridharan, S. S. P., Chen, Y. C., Patnaik, S., Safren, N., Hasegawa, J., de Haro, M., Gee, A. K. W., Titus, S. A., Jeong, H., Clarke, J., Krainc, D., Zheng, W., Irvine, R. F., Barmada, S., Ferrer, M., Southall, N., Weisman, L. S., Botas, J., & Marugan, J. J. (2017). Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein. eLife, 6, [e29123]. https://doi.org/10.7554/eLife.29123

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title = "Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein",

abstract = "The discovery of the causative gene for Huntington{\textquoteright}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{\textquoteright}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{\textquoteright}s disease, and potentially for other neurodegenerative disorders.",

author = "Ismael Al-Ramahi and Giridharan, {Sai Srinivas Panapakkam} and Chen, {Yu Chi} and Samarjit Patnaik and Nathaniel Safren and Junya Hasegawa and {de Haro}, Maria and Gee, {Amanda K.Wagner} and Titus, {Steven A.} and Hyunkyung Jeong and Jonathan Clarke and Dimitri Krainc and Wei Zheng and Irvine, {Robin F.} and Sami Barmada and Marc Ferrer and Noel Southall and Weisman, {Lois S.} and Juan Botas and Marugan, {Juan Jose}",

note = "Funding Information: Immortalized MEF wild-type and MEF Atg7 knock-out cells were a gift from Dr. Masaki Komatsu (Niigata University, Japan). None of the cell lines used in this study were included in the list of commonly misidentified cell lines maintained by International Cell Line Authentication Committee. This work was supported in part by National Institutes of Health (NIH) grants R01-NS064015 and R01-NS099340 to LSW, R01-NS097542 and P30-AG053760 to SJB, and the Protein Folding Diseases Fast Forward Initiative, University of Michigan to LSW and SJB. SSPG was supported in part by AHA Postdoctoral Fellowship, 14POST20480137. IA was supported by R21NS096395 grant from the NIH and by the Darrell K Royal Research Fund for Alzheimer{\textquoteright}s Disease. JB was supported by grants from the CHDI and the Robert A. and Ren{\'e}e E. Belfer Family Foundation. Publisher Copyright: {\textcopyright} Corsinotti et al.",

year = "2017",

month = dec,

day = "26",

doi = "10.7554/eLife.29123",

language = "English (US)",

volume = "6",

journal = "eLife",

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Al-Ramahi, I, Giridharan, SSP, Chen, YC, Patnaik, S, Safren, N, Hasegawa, J, de Haro, M, Gee, AKW, Titus, SA, Jeong, H, Clarke, J, Krainc, D, Zheng, W, Irvine, RF, Barmada, S, Ferrer, M, Southall, N, Weisman, LS, Botas, J & Marugan, JJ 2017, 'Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein', eLife, vol. 6, e29123. https://doi.org/10.7554/eLife.29123

TY - JOUR

T1 - Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein

AU - Al-Ramahi, Ismael

AU - Giridharan, Sai Srinivas Panapakkam

AU - Chen, Yu Chi

AU - Patnaik, Samarjit

AU - Safren, Nathaniel

AU - Hasegawa, Junya

AU - de Haro, Maria

AU - Gee, Amanda K.Wagner

AU - Titus, Steven A.

AU - Jeong, Hyunkyung

AU - Clarke, Jonathan

AU - Krainc, Dimitri

AU - Zheng, Wei

AU - Irvine, Robin F.

AU - Barmada, Sami

AU - Ferrer, Marc

AU - Southall, Noel

AU - Weisman, Lois S.

AU - Botas, Juan

AU - Marugan, Juan Jose

N1 - Funding Information: Immortalized MEF wild-type and MEF Atg7 knock-out cells were a gift from Dr. Masaki Komatsu (Niigata University, Japan). None of the cell lines used in this study were included in the list of commonly misidentified cell lines maintained by International Cell Line Authentication Committee. This work was supported in part by National Institutes of Health (NIH) grants R01-NS064015 and R01-NS099340 to LSW, R01-NS097542 and P30-AG053760 to SJB, and the Protein Folding Diseases Fast Forward Initiative, University of Michigan to LSW and SJB. SSPG was supported in part by AHA Postdoctoral Fellowship, 14POST20480137. IA was supported by R21NS096395 grant from the NIH and by the Darrell K Royal Research Fund for Alzheimer’s Disease. JB was supported by grants from the CHDI and the Robert A. and Renée E. Belfer Family Foundation. Publisher Copyright: © Corsinotti et al.

PY - 2017/12/26

Y1 - 2017/12/26

N2 - 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 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.

AB - 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 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.

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ER -

Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein

Abstract

ASJC Scopus subject areas

UN SDGs

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