1. Human Biology and Medicine
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Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein

  1. Ismael Al-Ramahi
  2. Sai Srinivas Panapakkam Giridharan
  3. Yu-Chi Chen
  4. Samarjit Patnaik
  5. Nathaniel Safren
  6. Junya Hasegawa
  7. Maria de Haro
  8. Amanda K Wagner Gee
  9. Steven A Titus
  10. Hyunkyung Jeong
  11. Jonathan Clarke
  12. Dimitri Krainc
  13. Wei Zheng
  14. Robin F Irvine
  15. Sami Barmada
  16. Marc Ferrer
  17. Noel Southall
  18. Lois S Weisman  Is a corresponding author
  19. Juan Botas  Is a corresponding author
  20. Juan Jose Marugan  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. University of Michigan, United States
  3. National Institutes of Health, United States
  4. Northwestern University, United States
  5. University of Cambridge, United Kingdom
Research Article
  • Cited 1
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Cite as: eLife 2017;6:e29123 doi: 10.7554/eLife.29123

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.

Article and author information

Author details

  1. Ismael Al-Ramahi

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Sai Srinivas Panapakkam Giridharan

    Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yu-Chi Chen

    National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Samarjit Patnaik

    National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Nathaniel Safren

    Department of Neurology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Junya Hasegawa

    Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-7041-890X
  7. Maria de Haro

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Amanda K Wagner Gee

    National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Steven A Titus

    National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Hyunkyung Jeong

    The Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Jonathan Clarke

    Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-4079-5333
  12. Dimitri Krainc

    The Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Wei Zheng

    National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Robin F Irvine

    Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Sami Barmada

    Department of Neurology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Marc Ferrer

    National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Noel Southall

    National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0003-4500-880X
  18. Lois S Weisman

    Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States
    For correspondence
    lweisman@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
  19. Juan Botas

    Baylor College of Medicine, Houston, United States
    For correspondence
    jbotas@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
  20. Juan Jose Marugan

    National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
    For correspondence
    maruganj@mail.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-3951-7061

Funding

National Institutes of Health (R01-NS064015)

  • Lois S Weisman

National Institutes of Health (R01-NS099340)

  • Lois S Weisman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All vertebrate animal work was approved by the Institutional Animal Use & Care Committee at the University of Michigan (PRO00007096).

Reviewing Editor

  1. Harry T Orr, Reviewing Editor, University of Minnesota, United States

Publication history

  1. Received: May 30, 2017
  2. Accepted: November 13, 2017
  3. Accepted Manuscript published: December 19, 2017 (version 1)
  4. Version of Record published: December 26, 2017 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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