1. Biochemistry and Chemical Biology
  2. Cell Biology
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Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract

  1. Koning Shen
  2. Barbara Calamini
  3. Jonathan A Fauerbach
  4. Boxue Ma
  5. Sarah H Shahmoradian
  6. Ivana L Serrano Lachapel
  7. Wah Chiu
  8. Donald C Lo
  9. Judith Frydman  Is a corresponding author
  1. Stanford University, United States
  2. Sanofi R&D, France
  3. Miltenyi Biotec, Germany
  4. Baylor College of Medicine, United States
  5. Paul Scherrer Institute, Switzerland
  6. Duke University Medical Center, United States
Research Article
  • Cited 29
  • Views 2,696
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Cite this article as: eLife 2016;5:e18065 doi: 10.7554/eLife.18065

Abstract

Many neurodegenerative diseases are linked to amyloid aggregation. In Huntington's disease (HD), neurotoxicity correlates with increased aggregation propensity of a polyglutamine (polyQ) expansion in exon 1 of mutant huntingtin protein (mHtt). Here we establish how the domains flanking the polyQ tract shape the mHtt conformational landscape in vitro and in neurons. In vitro, the flanking domains have opposing effects on the conformation and stabilities of oligomers and amyloid fibrils. The N-terminal N17 promotes amyloid fibril formation, while the C-terminal Proline Rich Domain destabilizes fibrils and enhances oligomer formation. However, in neurons both domains act synergistically to engage protective chaperone and degradation pathways promoting mHtt proteostasis. Surprisingly, when proteotoxicity was assessed in rat corticostriatal brain slices, either flanking region alone sufficed to generate a neurotoxic conformation, while the polyQ tract alone exhibited minimal toxicity. Linking mHtt structural properties to its neuronal proteostasis should inform new strategies for neuroprotection in polyQ-expansion diseases.

Article and author information

Author details

  1. Koning Shen

    Department of Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2607-449X
  2. Barbara Calamini

    Open Innovation Access Platform, Sanofi R&D, Strasbourg, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Jonathan A Fauerbach

    Miltenyi Biotec, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Boxue Ma

    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sarah H Shahmoradian

    Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Ivana L Serrano Lachapel

    Department of Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Wah Chiu

    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Donald C Lo

    Center for Drug Discovery, Department of Neurobiology, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Judith Frydman

    Department of Biology, Stanford University, Stanford, United States
    For correspondence
    jfrydman@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2302-6943

Funding

National Institute of General Medical Sciences (gm56433)

  • Koning Shen
  • Judith Frydman

National Institute of Neurological Disorders and Stroke (NS080514)

  • Barbara Calamini
  • Donald C Lo

NIH Office of the Director (pn2ey016525)

  • Sarah H Shahmoradian
  • Wah Chiu
  • Judith Frydman

National Institute of General Medical Sciences (gm103832)

  • Boxue Ma
  • Sarah H Shahmoradian
  • Wah Chiu

ellison medical foundation

  • Jonathan A Fauerbach
  • Judith Frydman

National Institute of Neurological Disorders and Stroke (NS092525)

  • Koning Shen
  • Judith Frydman

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

Ethics

Animal experimentation: No human subjects. Animals were handled and killed in accordance with NIH guidelines and under approval and oversight of the Duke University institutional animal care and use committee (IACUC) to Don Lo. Protocol number A147-14-06.

Reviewing Editor

  1. Jeffery W Kelly, The Scripps Research Institute, United States

Publication history

  1. Received: May 21, 2016
  2. Accepted: October 17, 2016
  3. Accepted Manuscript published: October 18, 2016 (version 1)
  4. Version of Record published: December 2, 2016 (version 2)

Copyright

© 2016, Shen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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