Recent studies suggest that brain cell type specific intracellular environments may play important roles in the generation of structurally different protein aggregates that define neurodegenerative diseases. Using human induced pluripotent stem cells (hiPSC) and biochemical and vibrational spectroscopy techniques, we studied whether Parkinson’s disease (PD) patient genomes could modulate alpha-synuclein (aSYN) protein aggregates formation. We found increased β-sheets and aggregated aSYN in PD patient hiPSC-derived midbrain cells, compared to controls. Importantly, we discovered that aSYN protein aggregation is modulated by patient brain cells’ intracellular milieus at the primary nucleation phase. Additionally, we found changes in the formation of aSYN fibrils when employing cellular extracts from familial PD compared to idiopathic PD, in a Thioflavin T-based fluorescence assay. The data suggest that changes in cellular milieu induced by patient genomes trigger structural changes of aSYN potentially leading to the formation of strains having different structures, properties and seeding propensities.

中文翻译：

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帕金森病患者脑细胞的细胞内环境调节 α-突触核蛋白聚集

最近的研究表明，脑细胞类型特定的细胞内环境可能在定义神经退行性疾病的结构不同的蛋白质聚集体的产生中发挥重要作用。使用人类诱导多能干细胞 (hiPSC) 和生化和振动光谱技术，我们研究了帕金森病 (PD) 患者基因组是否可以调节 α-突触核蛋白 (aSYN) 蛋白聚集体的形成。与对照组相比，我们发现 PD 患者 hiPSC 衍生的中脑细胞中 β-折叠和聚集的 aSYN 增加。重要的是，我们发现 aSYN 蛋白聚集在初级成核阶段受患者脑细胞的细胞内环境调节。此外，我们发现与特发性 PD 相比，使用家族性 PD 的细胞提取物时，aSYN 原纤维的形成发生了变化，在基于硫黄素 T 的荧光测定中。数据表明，由患者基因组诱导的细胞环境变化引发了 aSYN 的结构变化，可能导致形成具有不同结构、特性和播种倾向的菌株。