Pathogenesis and Control of Chronic Infections, Etablissement Français du Sang, INSERM, Université de Montpellier, Montpellier, France.
French Agency for Food, Environmental, and Occupational Health and Safety (ANSES), University of Lyon, Lyon, France.
FASEB J. 2019 Nov;33(11):12073-12086. doi: 10.1096/fj.201900354R. Epub 2019 Aug 1.
α-Synuclein (α-syn) protein aggregation is associated with several neurodegenerative disorders collectively referred to as synucleinopathies, including Parkinson's disease. We used protein misfolding cyclic amplification (PMCA) to study α-syn aggregation in brain homogenates of wild-type or transgenic mice expressing normal (D line) or A53T mutant (M83 line) human α-syn. We found that sonication-incubation cycles of M83 mouse brain gradually produce large quantities of SDS-resistant α-syn aggregates, involving both human and mouse proteins. These PMCA products, containing partially proteinase K-resistant α-syn species, are competent to accelerate the onset of neurologic symptoms after intracerebral inoculation to young M83 mice and to seed aggregate formation of α-syn following PMCA, including in D and wild-type mouse brain substrates. PMCA seeding activity in the M83 diseased brain correlates positively with regions mostly targeted by the α-syn pathology in this model. Our data indicate that similar to prions, PMCA can reproduce some characteristics of α-syn aggregation and seeded propagation in a complex milieu. This opens new opportunities for the molecular study of synucleinopathies.-Nicot, S., Verchère, J., Bélondrade, M., Mayran, C., Bétemps, D., Bougard, D., Baron, T. Seeded propagation of α-synuclein aggregation in mouse brain using protein misfolding cyclic amplification.
α-突触核蛋白（α-syn）的聚集与几种神经退行性疾病有关，这些疾病统称为突触核蛋白病，包括帕金森病。我们使用蛋白质错误折叠循环扩增（PMCA）技术研究了表达正常（D 线）或 A53T 突变（M83 线）人α-syn 的野生型或转基因小鼠的脑匀浆中的α-syn 聚集。我们发现，M83 小鼠脑的超声孵育循环逐渐产生大量的 SDS 抗性α-syn 聚集物，涉及人和鼠蛋白。这些 PMCA 产物含有部分蛋白酶 K 抗性的α-syn 物种，具有在脑内接种后加速年轻 M83 小鼠神经症状发作的能力，并在 PMCA 后引发α-syn 的聚集形成，包括在 D 和野生型小鼠脑底物中。M83 患病脑中的 PMCA 接种活性与该模型中α-syn 病理学主要靶向的区域呈正相关。我们的数据表明，类似于朊病毒，PMCA 可以在复杂的环境中复制α-syn 聚集和接种传播的一些特征。这为突触核蛋白病的分子研究开辟了新的机会。-Nicot, S., Verchère, J., Bélondrade, M., Mayran, C., Bétemps, D., Bougard, D., Baron, T. 使用蛋白质错误折叠循环扩增在小鼠脑中进行α-突触核蛋白聚集的接种传播。
