α-Synuclein protein (α-syn) is a central player in Parkinson's disease (PD) and in a spectrum of neurodegenerative diseases collectively known as synucleinopathies. These diseases are characterized by abnormal motor symptoms, such as tremor at rest, slowness of movement, rigidity of posture, and bradykinesia. Histopathological features of PD include preferential loss of dopaminergic neurons in the substantia nigra and formation of fibrillar intraneuronal inclusions called Lewy bodies and Lewy neurites, which are composed primarily of the α-syn protein. Currently, it is well accepted that α-syn oligomers (αSO) are the main toxic agent responsible for the etiology of PD. Glutamatergic excitotoxicity is associated with several neurological disorders, including PD. Excess glutamate in the synaptic cleft can be taken up by the astrocytic glutamate transporters GLAST and GLT-1. Although this event is the main defense against glutamatergic excitotoxicity, the molecular mechanisms that regulate this process have not yet been investigated in an early sporadic model of synucleinopathy. Here, using an early sporadic model of synucleinopathy, we demonstrated that the treatment of astrocytes with αSO increased glutamate uptake. This was associated with higher levels of GLAST and GLT-1 in astrocyte cultures and in a mouse model of synucleinopathy 24 h and 45 days after inoculation with αSO, respectively. Pharmacological inhibition of the TGF-β1 (transforming growth factor beta 1) pathway in vivo reverted GLAST/GLT-1 enhancement induced by αSO injection. Therefore, our study describes a new neuroprotective role of astrocytes in an early sporadic model of synucleinopathy and sheds light on the mechanisms of glutamate transporter regulation for neuroprotection against glutamatergic excitotoxicity in synucleinopathy.

α-突触核蛋白 (α-syn) 是帕金森病 (PD) 和一系列统称为突触核蛋白病的神经退行性疾病的核心参与者。这些疾病的特征在于异常运动症状，例如静止时震颤、运动缓慢、姿势僵硬和运动迟缓。PD 的组织病理学特征包括黑质中多巴胺能神经元的优先丢失纤维状神经元内包涵体的形成，称为路易体和路易轴突，它们主要由 α-syn 蛋白组成。目前，人们普遍认为 α-syn 寡聚体 (αSO) 是导致 PD 病因的主要毒剂。谷氨酸能兴奋性毒性与多种神经系统疾病有关，包括 PD。突触间隙中过量的谷氨酸可以被星形胶质细胞谷氨酸转运蛋白 GLAST 和 GLT-1 吸收。尽管此事件是对抗谷氨酸能兴奋性毒性的主要防御措施，但尚未在突触核蛋白病的早期散发模型中研究调节此过程的分子机制。在这里，使用突触核蛋白病的早期散发模型，我们证明了用 αSO 治疗星形胶质细胞会增加谷氨酸摄取。这与分别在接种αSO 24 小时和45 天后星形胶质细胞培养物和突触核蛋白病小鼠模型中GLAST 和GLT-1 水平升高有关。TGF-β1（转化生长因子β1）途径的药理学抑制体内恢复了αSO 注射诱导的 GLAST/GLT-1 增强。因此，我们的研究描述了星形胶质细胞在突触核蛋白病早期散发模型中的新神经保护作用，并阐明了谷氨酸转运蛋白调节对突触核蛋白病中谷氨酸能兴奋性毒性的神经保护机制。