Niskanen Jonna, Peltonen Sanni, Ohtonen Sohvi, Fazaludeen Mohammad Feroze, Luk Kelvin C, Giudice Luca, Koistinaho Jari, Malm Tarja, Goldsteins Gundars, Albert Katrina, Lehtonen Šárka
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
Glia. 2025 Jan;73(1):159-174. doi: 10.1002/glia.24626. Epub 2024 Oct 22.
Microglia are brain resident immune cells that maintain proteostasis and cellular homeostasis. Recent findings suggest that microglia dysfunction could contribute to the pathogenesis of Parkinson's disease (PD). One of the hallmarks of PD is the aggregation and accumulation of alpha-synuclein (αSyn) into Lewy bodies inside nerve cells. Microglia may worsen the neuronal microenvironment by persistent inflammation, resulting in deficient clearing of aggregated αSyn. To model microglial behavior in PD, we utilized human induced pluripotent stem cells to generate functionally active microglia. We studied the microglial uptake of alpha-synuclein preformed fibrils (PFFs) and the effect of pro-inflammatory stimulation by interferon gamma. We demonstrate that combined exposure disrupts the phagosome maturation pathway while inflammatory stimuli suppress chaperone mediated autophagy and mitochondrial function. Furthermore, inflammatory stimulation impairs PFF uptake in microglia and increases cytokine production. Moreover, excessive PFF uptake by microglia results in induction of inducible nitric oxide synthase. Taken together, we demonstrate that this model is valuable for investigating the behavior of microglia in PD and provide new insights on how human microglia process aggregated αSyn.
小胶质细胞是驻留在大脑中的免疫细胞，负责维持蛋白质稳态和细胞内环境稳定。最近的研究结果表明，小胶质细胞功能障碍可能导致帕金森病（PD）的发病机制。PD的一个标志是α-突触核蛋白（αSyn）在神经细胞内聚集并积累形成路易小体。小胶质细胞可能通过持续炎症恶化神经元微环境，导致聚集的αSyn清除不足。为了模拟PD中的小胶质细胞行为，我们利用人类诱导多能干细胞生成功能活跃的小胶质细胞。我们研究了小胶质细胞对α-突触核蛋白预形成纤维（PFFs）的摄取以及干扰素γ促炎刺激的影响。我们证明，联合暴露会破坏吞噬体成熟途径，而炎症刺激会抑制伴侣介导的自噬和线粒体功能。此外，炎症刺激会损害小胶质细胞对PFF的摄取并增加细胞因子的产生。此外，小胶质细胞过度摄取PFF会导致诱导型一氧化氮合酶的诱导。综上所述，我们证明该模型对于研究PD中小胶质细胞的行为具有重要价值，并为人类小胶质细胞如何处理聚集的αSyn提供了新的见解。
