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Elongator mutation in mice induces neurodegeneration and ataxia-like behavior

Author

Listed:
  • Marija Kojic

    (the University of Queensland)

  • Monika Gaik

    (Jagiellonian University)

  • Bence Kiska

    (the University of Queensland)

  • Anna Salerno-Kochan

    (Jagiellonian University
    Postgraduate School of Molecular Medicine)

  • Sarah Hunt

    (University of Queensland)

  • Angelo Tedoldi

    (University of Queensland)

  • Sergey Mureev

    (the University of Queensland)

  • Alun Jones

    (the University of Queensland)

  • Belinda Whittle

    (Australian National University)

  • Laura A. Genovesi

    (the University of Queensland)

  • Christelle Adolphe

    (the University of Queensland)

  • Darren L. Brown

    (the University of Queensland)

  • Jennifer L. Stow

    (the University of Queensland)

  • Kirill Alexandrov

    (the University of Queensland)

  • Pankaj Sah

    (University of Queensland)

  • Sebastian Glatt

    (Jagiellonian University)

  • Brandon J. Wainwright

    (the University of Queensland)

Abstract

Cerebellar ataxias are severe neurodegenerative disorders with an early onset and progressive and inexorable course of the disease. Here, we report a single point mutation in the gene encoding Elongator complex subunit 6 causing Purkinje neuron degeneration and an ataxia-like phenotype in the mutant wobbly mouse. This mutation destabilizes the complex and compromises its function in translation regulation, leading to protein misfolding, proteotoxic stress, and eventual neuronal death. In addition, we show that substantial microgliosis is triggered by the NLRP3 inflammasome pathway in the cerebellum and that blocking NLRP3 function in vivo significantly delays neuronal degeneration and the onset of ataxia in mutant animals. Our data provide a mechanistic insight into the pathophysiology of a cerebellar ataxia caused by an Elongator mutation, substantiating the increasing body of evidence that alterations of this complex are broadly implicated in the onset of a number of diverse neurological disorders.

Suggested Citation

  • Marija Kojic & Monika Gaik & Bence Kiska & Anna Salerno-Kochan & Sarah Hunt & Angelo Tedoldi & Sergey Mureev & Alun Jones & Belinda Whittle & Laura A. Genovesi & Christelle Adolphe & Darren L. Brown &, 2018. "Elongator mutation in mice induces neurodegeneration and ataxia-like behavior," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05765-6
    DOI: 10.1038/s41467-018-05765-6
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    Cited by:

    1. Aviel Even & Giovanni Morelli & Silvia Turchetto & Michal Shilian & Romain Le Bail & Sophie Laguesse & Nathalie Krusy & Ariel Brisker & Alexander Brandis & Shani Inbar & Alain Chariot & Frédéric Saudo, 2021. "ATP-citrate lyase promotes axonal transport across species," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Nour-el-Hana Abbassi & Marcin Jaciuk & David Scherf & Pauline Böhnert & Alexander Rau & Alexander Hammermeister & Michał Rawski & Paulina Indyka & Grzegorz Wazny & Andrzej Chramiec-Głąbik & Dominika D, 2024. "Cryo-EM structures of the human Elongator complex at work," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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