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The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice
Brain ( IF 10.6 ) Pub Date : 2017-09-06 , DOI: 10.1093/brain/awx221
Anna Migdalska-Richards 1 , Michal Wegrzynowicz 2 , Raffaella Rusconi 3 , Giulio Deangeli 2, 4, 5 , Donato A Di Monte 3 , Maria G Spillantini 2 , Anthony H V Schapira 1
Affiliation  

Mutations in glucocerebrosidase 1 (GBA1) represent the most prevalent risk factor for Parkinson’s disease. The molecular mechanisms underlying the link between GBA1 mutations and Parkinson’s disease are incompletely understood. We analysed two aged (24-month-old) Gba1 mouse models, one carrying a knock-out mutation and the other a L444P knock-in mutation. A significant reduction of glucocerebrosidase activity was associated with increased total alpha-synuclein accumulation in both these models. Gba1 mutations alone did not alter the number of nigral dopaminergic neurons nor striatal dopamine levels. We then investigated the effect of overexpression of human alpha-synuclein in the substantia nigra of aged (18 to 21-month-old) L444P Gba1 mice. Following intraparenchymal injections of human alpha-synuclein carrying viral vectors, pathological accumulation of phosphorylated alpha-synuclein occurred within the transduced neurons. Stereological counts of nigral dopaminergic neurons revealed a significantly greater cell loss in Gba1-mutant than wild-type mice. These results indicate that Gba1 deficiency enhances neuronal vulnerability to neurodegenerative processes triggered by increased alpha-synuclein expression.

中文翻译:

L444P Gba1突变增强了小鼠的α-突触核蛋白诱导的黑色素多巴胺能神经元的损失

葡萄糖脑苷脂酶1(GBA1)的突变代表帕金森氏病最普遍的危险因素。GBA1突变和帕金森氏病之间的联系的分子机制尚未完全了解。我们分析了两个年龄较大(24个月大)的Gba1小鼠模型,一个带有敲除突变,另一个带有L444P敲入突变。在这两个模型中,葡糖脑苷脂酶活性的显着降低与总α-突触核蛋白积累的增加有关。单独的Gba1突变不会改变黑色素多巴胺能神经元的数量,也不会改变纹状体多巴胺的水平。然后,我们调查了人α-突触核蛋白在老年(18至21个月大)L444P黑质中的过表达作用Gba1小鼠。在实质性内注射携带病毒载体的人α-突触核蛋白后,磷酸化的α-突触核蛋白的病理积累发生在被转导的神经元内。黑色素多巴胺能神经元的体视学计数显示,Gba1突变体中的细胞损失明显大于野生型小鼠。这些结果表明,Gba1缺乏症增加了神经元对由增加的α-突触核蛋白表达触发的神经退行性过程的脆弱性。
更新日期:2017-09-06
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