Elongator mutation in mice induces neurodegeneration and ataxia-like behavior

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, Jennifer L. Stow, Kirill Alexandrov, Pankaj Sah, Sebastian Glatt, Brandon J. Wainwright*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    38 Citations (Scopus)

    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.

    Original languageEnglish
    Article number3195
    JournalNature Communications
    Volume9
    Issue number1
    DOIs
    Publication statusPublished - 1 Dec 2018

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