2018
DOI: 10.1038/s41467-018-05765-6
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Elongator mutation in mice induces neurodegeneration and ataxia-like behavior

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… Show more

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Cited by 45 publications
(49 citation statements)
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“…We were able to demonstrate in these mice a severe motor phenotype that included deficits in motor coordination, grip or muscle strength, climbing and hanging behavior (in HCS), alterations in the walking pattern and hindlimb clasping. Behavioral traits such as altered walking pattern, hindlimb clasping and motor coordination deficits are usually observed in mouse models with an ataxia-like behavior and cerebellar dysfunctions (23,24). In agreement with these findings, ataxia was reported in some IGD patients and an ataxia-like behavior was observed in a conditional Piga knock out mouse model (10,19).…”
Section: Discussionsupporting
confidence: 66%
“…We were able to demonstrate in these mice a severe motor phenotype that included deficits in motor coordination, grip or muscle strength, climbing and hanging behavior (in HCS), alterations in the walking pattern and hindlimb clasping. Behavioral traits such as altered walking pattern, hindlimb clasping and motor coordination deficits are usually observed in mouse models with an ataxia-like behavior and cerebellar dysfunctions (23,24). In agreement with these findings, ataxia was reported in some IGD patients and an ataxia-like behavior was observed in a conditional Piga knock out mouse model (10,19).…”
Section: Discussionsupporting
confidence: 66%
“…The ASL modifications (c)t 6 A and mcm 5 (s 2 )U, found in yeast tRNAs respectively at positions 37 and 34, are critical for correct pre-structuring of the ASL [13][14][15][16][17]. Severe diseases in humans [18][19][20][21][22] and very similar phenotypes in yeast S. cerevisiae [3,29,37] are observed as a result of deficiencies in both these modifications. The sua5 elp3 mutant (lacking both t 6 A and mcm 5 U modifications), is viable in the YPD medium but cannot grow in the presence of various exogenous stressors such as elevated temperature, diamide or alternative carbon sources.…”
Section: Discussionmentioning
confidence: 99%
“…Early structural studies showed that t 6 A is crucial for the prevention of U33-A37 pairing, thus stabilizing the anticodon open-loop configuration, and that both modifications are critical for correct pre-structuring of the ASL [13][14][15][16][17]. Deficiencies in both these modifications lead to severe neurological diseases [18][19][20][21][22], and the yeast Saccharomyces cerevisiae has been a long-standing model to study their synthesis and function [23][24][25][26][27][28]. In yeast, t 6 A is found at position 37 of tRNAs that decode ANN codons and is further modified to ct 6 A in several tRNAs such as tRNA Lys UUU [29,30].…”
Section: Introductionmentioning
confidence: 99%
“…Specifically, wb Purkinje cells are less excitable showing increased resting membrane potential and action potential threshold. Parallel fiber stimulation fails to evoke excitatory synaptic currents in more than 50% of Purkinje cells, while evoked synaptic inhibition is shown to be stronger [55]. Later, another dominant mutation, known as Tg-5J, in CACNA1A gene, resembling the wobby and many human mutations, was described by Miki and coworkers [56].…”
Section: Mutations In the Cacna1a Genementioning
confidence: 99%
“…In 2007, however, Xie and colleagues reported the first dominant ataxic mouse model of CACNA1A mutation, called Wobbly (wb) on the basis of its peculiar gait [54]. Heterozygotes show severe ataxia and reduced locomotor activity with associated degeneration of Purkinje cells [54,55]. Purkinje cells display altered passive and active membrane properties and an altered synaptic excitation/inhibition balance in wb mice.…”
Section: Mutations In the Cacna1a Genementioning
confidence: 99%