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 () and Brandon J. Wainwright ()
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Marija Kojic: the University of Queensland
Monika Gaik: Jagiellonian University
Bence Kiska: the University of Queensland
Anna Salerno-Kochan: Jagiellonian University
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

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05765-6

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