Parkinson’s disease (PD) is the second most common neurodegenerative disease, following Alzheimer’s. It is characterized by the aggregation of α-synuclein into Lewy bodies and Lewy neurites in the brain. Microglia-driven neuroinflammation may contribute to neuronal death in PD; however, the exact role of microglia remains unclear and has been understudied. The A53T mutation in the gene coding for α-synuclein has been linked to early-onset PD, and exposure to A53T mutant human α-synuclein increases the potential for inflammation of murine microglia. To date, its effect has not been studied in human microglia. Here, we used 2-dimensional cultures of human pluripotent stem cell–derived microglia and transplantation of these cells into the mouse brain to assess the cell autonomous effects of the A53T mutation on human microglia. We found that A53T mutant human microglia had an intrinsically increased propensity toward proinflammatory activation upon inflammatory stimulus. Additionally, transplanted A53T mutant microglia showed a strong decrease in catalase expression in noninflammatory conditions and increased oxidative stress. Our results indicate that A53T mutant human microglia display cell autonomous phenotypes that may worsen neuronal damage in early-onset PD.

中文翻译：

---

α-突触核蛋白的 A53T 突变增强人类小胶质细胞在炎症刺激下的促炎激活


帕金森病 (PD) 是继阿尔茨海默病之后第二常见的神经退行性疾病。其特征是α-突触核蛋白在大脑中聚集成路易体和路易神经突。小胶质细胞驱动的神经炎症可能导致帕金森病中的神经元死亡；然而，小胶质细胞的确切作用仍不清楚，并且尚未得到充分研究。编码 α-突触核蛋白的基因中的 A53T 突变与早发性帕金森病有关，接触 A53T 突变的人 α-突触核蛋白会增加小鼠小胶质细胞发生炎症的可能性。迄今为止，尚未在人类小胶质细胞中研究其作用。在这里，我们使用人类多能干细胞衍生的小胶质细胞的二维培养物并将这些细胞移植到小鼠大脑中，以评估 A53T 突变对人类小胶质细胞的细胞自主影响。我们发现 A53T 突变的人类小胶质细胞在炎症刺激下具有内在增加的促炎激活倾向。此外，移植的 A53T 突变型小胶质细胞在非炎症条件下表现出过氧化氢酶表达的强烈下降和氧化应激的增加。我们的结果表明，A53T 突变的人类小胶质细胞表现出细胞自主表型，可能会加重早发性 PD 的神经元损伤。