Molecular and functional features of synucleinopathy-associated astrocytes

Astrocyte (AC) involvement is a common neuropathological feature in human synucleinopathy-associated neurodegeneration. However, our understanding of the in vivo characteristics of reactive ACs in synucleinopathy remained limited. Here we report the transcriptomic and functional features of a unique synucleinopathy-associated AC (SAA) subtype in a mouse model. SAAs share a convergent transcriptomic state across synucleinopathy-laden brain regions, and are at least partially reliant on microglia for their phenotypic maintenance in vivo. Intravital imaging revealed that an upregulation of the excitatory amino acid transporter 2 (EAAT2) in synucleinopathy-affected ACs is associated with depressed neuronal activities. This is potentially mediated via increased AC glutamate uptake, as pharmacological induction of EAAT2 reproduced the same effect. With cross-species comparative analysis, we showed that the core SAA transcriptomic features are present in human aged and synucleinopathy-affected midbrain ACs, while important distinct characteristics also exist. Collectively, our results uncovered complex reactive AC changes that likely play important adaptive roles in synucleinopathy.星形胶质细胞（Astrocyte, AC）受累是人类突触核蛋白病相关神经退行性疾病中常见的神经病理特征。然而，目前我们对突触核蛋白病中反应性星形胶质细胞的在体特征的认知仍较为有限。本研究在小鼠模型中报道了一种独特的、与突触核蛋白病相关的星形胶质细胞（synucleinopathy-associated AC, SAA）亚型的转录组学与功能特征。SAAs在携带突触核蛋白病的脑区中呈现趋同的转录组状态，且其体内表型维持至少部分依赖小胶质细胞。活体成像显示，在受突触核蛋白病累及的星形胶质细胞中，兴奋性氨基酸转运体2（excitatory amino acid transporter 2, EAAT2）的表达上调与神经元活动受抑制相关。这一效应可能通过增强星形胶质细胞的谷氨酸摄取实现：药理学诱导EAAT2表达可重现相同的神经元活动抑制效果。通过跨物种比较分析，我们发现SAAs的核心转录组特征存在于人类衰老且受突触核蛋白病累及的中脑星形胶质细胞中，但同时也存在重要的独特差异特征。综上，本研究揭示了复杂的反应性星形胶质细胞改变，这类改变可能在突触核蛋白病中发挥重要的适应性作用。