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Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress

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  • Julia Leitman

    (George Wise Faculty of Life Sciences, Tel Aviv University)

  • F. Ulrich Hartl

    (Max Planck Institute of Biochemistry)

  • Gerardo Z. Lederkremer

    (George Wise Faculty of Life Sciences, Tel Aviv University)

Abstract

In Huntington’s disease, as in other neurodegenerative diseases, it was initially thought that insoluble protein aggregates are the toxic species. However, growing evidence implicates soluble oligomeric polyglutamine-expanded huntingtin in cytotoxicity. Here we show that pathogenic huntingtin inhibits endoplasmic reticulum (ER)-associated degradation and induces ER stress before its aggregation into visible inclusions. All three branches of the unfolded protein response are activated. ER stress can be compensated by overexpression of p97/VCP, suggesting its sequestration by pathogenic huntingtin as a main cause. Stress correlates with the presence of huntingtin oligomers and is independent of continual huntingtin synthesis. Stress levels, measured in striatal neurons, are stabilized but only slowly subside on huntingtin aggregation into inclusions. Our results can be explained by the constant conversion of huntingtin monomers to toxic oligomers; large aggregates sequester the former, precluding further conversion, whereas pre-existing toxic oligomers are only gradually depleted.

Suggested Citation

  • Julia Leitman & F. Ulrich Hartl & Gerardo Z. Lederkremer, 2013. "Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress," Nature Communications, Nature, vol. 4(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3753
    DOI: 10.1038/ncomms3753
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    Cited by:

    1. Nathan Riguet & Anne-Laure Mahul-Mellier & Niran Maharjan & Johannes Burtscher & Marie Croisier & Graham Knott & Janna Hastings & Alice Patin & Veronika Reiterer & Hesso Farhan & Sergey Nasarov & Hila, 2021. "Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties," Nature Communications, Nature, vol. 12(1), pages 1-27, December.
    2. Sarah Rösing & Fabian Ullrich & Susann Meisterfeld & Franziska Schmidt & Laura Mlitzko & Marijana Croon & Ryan G Nattrass & Nadia Eberl & Julia Mahlberg & Martin Schlee & Anja Wieland & Philipp Simon , 2024. "Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Bankanidhi Sahoo & Irene Arduini & Kenneth W Drombosky & Ravindra Kodali & Laurie H Sanders & J Timothy Greenamyre & Ronald Wetzel, 2016. "Folding Landscape of Mutant Huntingtin Exon1: Diffusible Multimers, Oligomers and Fibrils, and No Detectable Monomer," PLOS ONE, Public Library of Science, vol. 11(6), pages 1-22, June.

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