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Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration.
Nature Neuroscience ( IF 21.2 ) Pub Date : 2017-09-18 , DOI: 10.1038/nn.4641
Danielle E Mor 1 , Elpida Tsika 2 , Joseph R Mazzulli 3 , Neal S Gould 4 , Hanna Kim 5 , Malcolm J Daniels 6 , Shachee Doshi 1 , Preetika Gupta 1 , Jennifer L Grossman 7 , Victor X Tan 8 , Robert G Kalb 1, 4 , Kim A Caldwell 5 , Guy A Caldwell 5 , John H Wolfe 1, 4, 9 , Harry Ischiropoulos 1, 4, 6
Affiliation  

Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and α-synuclein aggregation.

中文翻译:


多巴胺诱导可溶性 α-突触核蛋白寡聚体和黑质纹状体变性。



帕金森病 (PD) 的定义是黑质中多巴胺能神经元的丧失以及含有聚集的 α-突触核蛋白的路易体包涵体的形成。由于α-突触核蛋白转基因小鼠缺乏多巴胺能细胞死亡,解释多巴胺神经元脆弱性的努力受到阻碍。为了解决这个问题,我们操纵多巴胺水平和 α-突触核蛋白表达。催化活性增强的突变酪氨酸羟化酶的黑质靶向表达增加了多巴胺水平,而不损害非转基因小鼠的神经元。相反,提高表达人 A53T 突变体 α-突触核蛋白的小鼠的多巴胺水平会诱导进行性黑质纹状体变性并减少运动。 A53T 小鼠中多巴胺的升高增加了潜在有毒的 α-突触核蛋白寡聚体的水平,导致构象和功能发生改变。此外,在遗传易处理的秀丽隐杆线虫模型中,α-突触核蛋白在与多巴胺相互作用位点的表达突变可以防止多巴胺诱导的毒性。这些数据表明,一种独特的机制将 PD 的两个主要特征联系在一起:多巴胺能细胞死亡和 α-突触核蛋白聚集。
更新日期:2017-09-19
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