Elongator mutation in mice induces neurodegeneration and ataxia-like behavior

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.The authors acknowledge the facilities, and the scientific and technical assistance of the Australian Phenomics Facility (APF), the Australian National University. The APF is supported by the Australian Phenomics Network (APN). The APN is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. We are very grateful to Jelena Bezbradica Mirkovic and Kate Schroder for providing NLRP3 KO and Caspase-1 KO animals and for their valuable discussion. We also thank Avril Robertson and Matthew Cooper for the gift of MCC950 and Trent Woodruff for advice regarding the administration of MCC950. We acknowledge Ting-Yu Lin and Andrzej Chramiec-Głąbik for providing labeled tRNAs. This work was supported by the POLONEZ1 Grant UMO-2015/19/P/NZ1/02514 from the National Science Centre, Poland and received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 665778 (M.G. and A.S.-K.) and the First Team grant First TEAM/ 2016-1/2 from the Foundation for Polish Science (S.G.)