The progressive neuropathological damage seen in Parkinson's disease (PD) is thought to be related to the spreading of aggregated forms of α‐synuclein. Clearance of extracellular α‐synuclein released by degenerating neurons may be therefore a key mechanism to control the concentration of α‐synuclein in the extracellular space. Several molecular chaperones control misfolded protein accumulation in the extracellular compartment. Among these, clusterin, a glycoprotein associated with Alzheimer's disease, binds α‐synuclein aggregated species and is present in Lewy bodies, intraneuronal aggregates mainly composed by fibrillary α‐synuclein. In this study, using murine primary astrocytes with clusterin genetic deletion, human‐induced pluripotent stem cell (iPSC)‐derived astrocytes with clusterin silencing and two animal models relevant for PD we explore how clusterin affects the clearance of α‐synuclein aggregates by astrocytes. Our findings showed that astrocytes take up α‐synuclein preformed fibrils (pffs) through dynamin‐dependent endocytosis and that clusterin levels are modulated in the culture media of cells upon α‐synuclein pffs exposure. Specifically, we found that clusterin interacts with α‐synuclein pffs in the extracellular compartment and the clusterin/α‐synuclein complex can be internalized by astrocytes. Mechanistically, using clusterin knock‐out primary astrocytes and clusterin knock‐down hiPSC‐derived astrocytes we observed that clusterin limits the uptake of α‐synuclein pffs by cells. Interestingly, we detected increased levels of clusterin in the adeno‐associated virus‐ and the α‐synuclein pffs‐ injected mouse model, suggesting a crucial role of this chaperone in the pathogenesis of PD. Overall, our observations indicate that clusterin can limit the uptake of extracellular α‐synuclein aggregates by astrocytes and, hence, contribute to the spreading of Parkinson pathology.

中文翻译：

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细胞外凝聚素限制了小鼠和人类星形胶质细胞对 α-突触核蛋白原纤维的摄取

在帕金森病 (PD) 中观察到的进行性神经病理学损伤被认为与 α-​​突触核蛋白聚集形式的扩散有关。因此，清除退化神经元释放的细胞外α-突触核蛋白可能是控制细胞外空间中α-突触核蛋白浓度的关键机制。几种分子伴侣控制细胞外区室中错误折叠的蛋白质积累。其中，凝聚素是一种与阿尔茨海默病相关的糖蛋白，与 α-突触核蛋白聚集体结合，存在于路易小体中，路易体是主要由纤维状 α-突触核蛋白组成的神经元内聚集体。在这项研究中，使用具有凝聚素基因缺失的小鼠原代星形胶质细胞，人类诱导多能干细胞 (iPSC) 衍生的星形胶质细胞具有凝聚素沉默和两个与 PD 相关的动物模型，我们探讨凝聚素如何影响星形胶质细胞清除 α-突触核蛋白聚集体。我们的研究结果表明，星形胶质细胞通过依赖于动力蛋白的内吞作用摄取 α-突触核蛋白预制原纤维 (pffs)，并且在 α-突触核蛋白 pffs 暴露后，细胞培养基中的凝聚素水平受到调节。具体来说，我们发现凝聚素与细胞外区室中的 α-突触核蛋白 pffs 相互作用，并且凝聚素/α-突触核蛋白复合物可以被星形胶质细胞内化。从机制上讲，使用凝聚素敲除原代星形胶质细胞和凝聚素敲除 hiPSC 衍生的星形胶质细胞，我们观察到凝聚素限制了细胞对 α-突触核蛋白 pffs 的摄取。有趣的是，我们在腺相关病毒和 α-突触核蛋白 pffs 注射的小鼠模型中检测到聚集蛋白水平升高，表明该伴侣蛋白在 PD 发病机制中的关键作用。总的来说，我们的观察表明，凝聚素可以限制星形胶质细胞对细胞外 α-突触核蛋白聚集体的摄取，因此有助于帕金森病的传播。