α-Synuclein (α-Syn)-positive intracellular fibrillar protein deposits, known as Lewy bodies, are thought to be involved in the pathogenesis of Parkinson's disease (PD). Although recent lines of evidence suggested that extracellular α-Syn secreted from pathogenic neurons contributes to the propagation of PD pathology, the precise mechanism of action remains unclear. We have reported that extracellular α-Syn caused sphingosine 1-phosphate (S1P) receptor type 1 (S1PR1) uncoupled from Gi and inhibited downstream G-protein signaling in SH-SY5Y cells, although its patho/physiological role remains to be clarified. Here we show that extracellular α-Syn caused S1P receptor type 3 (S1PR3) uncoupled from G protein in HeLa cells. Further studies indicated that α-Syn treatment reduced cathepsin D activity while enhancing the secretion of immature pro-cathepsin D into cell culture medium, suggesting that lysosomal delivery of cathepsin D was disturbed. Actually, extracellular α-Syn attenuated the retrograde trafficking of insulin-like growth factor-II/mannose 6-phosphate (IGF-II/M6P) receptor, which is under the regulation of S1PR3. These findings shed light on the understanding of dissemination of the PD pathology, that is, the mechanism underlying how extracellular α-Syn secreted from pathogenic cells causes lysosomal dysfunction of the neighboring healthy cells, leading to propagation of the disease.

中文翻译：

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细胞外 α-突触核蛋白损害 HeLa 细胞中 1-磷酸鞘氨醇受体 3 型 (S1PR3) 调节的组织蛋白酶 D 的溶酶体递送

α-突触核蛋白 (α-Syn) 阳性细胞内纤维蛋白沉积物（称为路易体）被认为与帕金森病 (PD) 的发病机制有关。尽管最近的证据表明致病神经元分泌的细胞外 α-Syn 有助于 PD 病理学的传播，但其确切的作用机制仍不清楚。我们报道，细胞外 α-Syn 导致 1-磷酸鞘氨醇 (S1P) 受体 1 型 (S1PR1) 与 Gi 解偶联，并抑制 SH-SY5Y 细胞中的下游 G 蛋白信号传导，尽管其病理/生理作用仍有待阐明。在这里，我们发现细胞外 α-Syn 导致 HeLa 细胞中的 S1P 受体 3 (S1PR3) 与 G 蛋白解偶联。进一步的研究表明，α-Syn 处理降低了组织蛋白酶 D 活性，同时增强了未成熟的组织蛋白酶 D 原分泌到细胞培养基中，这表明组织蛋白酶 D 的溶酶体递送受到干扰。实际上，细胞外的 α-Syn 减弱了胰岛素样生长因子-II/甘露糖 6-磷酸 (IGF-II/M6P) 受体的逆行运输，而该受体受 S1PR3 的调节。这些发现有助于理解PD病理学的传播，即致病细胞分泌的细胞外α-Syn如何引起邻近健康细胞的溶酶体功能障碍，从而导致疾病传播的机制。