SLC1A5 variant (SLC1A5_var) is identified as a mitochondrial glutamine transporter in cancer cells recently. However, the role of SLC1A5_var in Parkinson’s disease (PD) is completely unknown. Here, we found the significant downregulation of SLC1A5_var in astrocytes and midbrain of mice treated with MPTP/MPP⁺ and LPS. Importantly, overexpression of SLC1A5_var ameliorated but knockdown of SLC1A5_var exacerbated MPTP/MPP⁺- and LPS-induced mitochondrial dysfunction. Consequently, SLC1A5_var provided beneficial effects on PD pathology including improvement of PD-like motor symptoms and rescue of dopaminergic (DA) neuron degeneration through maintaining mitochondrial energy metabolism. Moreover, SLC1A5_var reduced astrocyte reactivity via inhibition of A1 astrocyte conversion. Further investigation demonstrated that SLC1A5_var restrained the secretion of astrocytic pro-inflammatory cytokines by blunting TLR4-mediated downstream pathways. This is the first study to prove that astrocytic SLC1A5_var inhibits neuroinflammation, and rescues the loss of DA neurons and motor symptoms involved in PD progression, which provides a novel target for PD treatment.

SLC1A5 变体 (SLC1A5_var) 最近被鉴定为癌细胞中的线粒体谷氨酰胺转运蛋白。然而，SLC1A5_var 在帕金森病 (PD) 中的作用完全未知。^{在这里，我们发现在用 MPTP/MPP +}和 LPS处理的小鼠星形胶质细胞和中脑中 SLC1A5_var 显着下调。重要的是，SLC1A5_var 的过表达得到改善，但 SLC1A5_var 的敲低加剧了 MPTP/MPP ⁺- 和 LPS 诱导的线粒体功能障碍。因此，SLC1A5_var 对 PD 病理学产生有益影响，包括改善 PD 样运动症状和通过维持线粒体能量代谢来挽救多巴胺能 (DA) 神经元变性。此外，SLC1A5_var 通过抑制 A1 星形胶质细胞转化来降低星形胶质细胞的反应性。进一步的研究表明，SLC1A5_var 通过减弱 TLR4 介导的下游通路来抑制星形胶质细胞促炎细胞因子的分泌。这是第一项证明星形胶质细胞SLC1A5_var抑制神经炎症，挽救PD进展过程中多巴胺神经元丢失和运动症状的研究，为PD治疗提供了新的靶点。