Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity.
Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity.
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DOI：
10.1186/s40478-018-0554-9
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发表时间：
2018-07-02
影响因子：
7.1
通讯作者：
Sorensen PH
中科院分区：
文献类型：
--
作者：
Jan A;Jansonius B;Delaidelli A;Bhanshali F;An YA;Ferreira N;Smits LM;Negri GL;Schwamborn JC;Jensen PH;Mackenzie IR;Taubert S;Sorensen PH
帕金森病(PD)是第二常见的神经退行性疾病，也是导致运动障碍的主要神经退行性疾病。帕金森病的特点是大脑中聚集的α-突触核蛋白(AS)的病理性积聚，以及由于黑质致密部多巴胺能神经元的丢失导致黑质纹状体系统的失衡。聚集和繁殖被认为是帕金森病神经毒性机制的触发因素，包括线粒体缺陷和氧化应激。真核细胞延长因子-2激酶(EEF2K)介导树突状细胞mRNA翻译的关键调控，是多种形式突触可塑性的关键分子。在这里，我们显示，通过免疫组织化学检测eEF2丝氨酸残基56的磷酸化来评估eEF2K活性，在死后PD的中脑和海马区，eEF2K活性增加。在转基因PD M83小鼠模型中诱导攻击性的AS相关运动表型也增加了脑eEF2K的表达和活性。在培养的多巴胺能N2A细胞中，野生型人AS或A53T突变体的过表达增加了eEF2K的活性。EEF2K抑制通过改善线粒体功能和减少氧化应激来防止与AS过度表达相关的细胞毒性。此外，线虫中eEF2K同源基因efk-1的基因缺失减弱了人类A53T，因为这是依赖于多巴胺能神经元功能的行为分析中的诱导缺陷。这些数据提示eEF2K活性在AS毒性中的作用，并支持eEF2K抑制作为减少As诱导的PD氧化应激的潜在靶点。本文的在线版本(10.1186/s40478-0180554-9)包含补充材料，可供授权用户使用。
Parkinson disease (PD) is the second most common neurodegenerative disorder and the leading neurodegenerative cause of motor disability. Pathologic accumulation of aggregated alpha synuclein (AS) protein in brain, and imbalance in the nigrostriatal system due to the loss of dopaminergic neurons in the substantia nigra- pars compacta, are hallmark features in PD. AS aggregation and propagation are considered to trigger neurotoxic mechanisms in PD, including mitochondrial deficits and oxidative stress. The eukaryotic elongation factor-2 kinase (eEF2K) mediates critical regulation of dendritic mRNA translation and is a crucial molecule in diverse forms of synaptic plasticity. Here we show that eEF2K activity, assessed by immuonohistochemical detection of eEF2 phosphorylation on serine residue 56, is increased in postmortem PD midbrain and hippocampus. Induction of aggressive, AS-related motor phenotypes in a transgenic PD M83 mouse model also increased brain eEF2K expression and activity. In cultures of dopaminergic N2A cells, overexpression of wild-type human AS or the A53T mutant increased eEF2K activity. eEF2K inhibition prevented the cytotoxicity associated with AS overexpression in N2A cells by improving mitochondrial function and reduced oxidative stress. Furthermore, genetic deletion of the eEF2K ortholog efk-1 in C. elegans attenuated human A53T AS induced defects in behavioural assays reliant on dopaminergic neuron function. These data suggest a role for eEF2K activity in AS toxicity, and support eEF2K inhibition as a potential target in reducing AS-induced oxidative stress in PD. The online version of this article (10.1186/s40478-018-0554-9) contains supplementary material, which is available to authorized users.
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影响因子：
16.2
作者：
Giasson, BI;Duda, JE;Lee, VMY
通讯作者：
Lee, VMY
影响因子：
7.1
作者：
Garcia-Esparcia P;Hernández-Ortega K;Koneti A;Gil L;Delgado-Morales R;Castaño E;Carmona M;Ferrer I
通讯作者：
Ferrer I
影响因子：
5.3
作者：
Heise C;Gardoni F;Culotta L;di Luca M;Verpelli C;Sala C
通讯作者：
Sala C
影响因子：
2.5
作者：
JANETZKY, B;HAUCK, S;REICHMANN, H
通讯作者：
REICHMANN, H
DOI：
10.1007/978-3-319-43589-3_7
发表时间：
2016-01-01
期刊：
AMP-ACTIVATED PROTEIN KINASE
影响因子：
--
作者：
Domise, Manon;Vingtdeux, Valerie
通讯作者：
Vingtdeux, Valerie