Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy.
Department of Biology, University of Padova, 35131 Padova, Italy.
Int J Mol Sci. 2023 Aug 10;24(16):12656. doi: 10.3390/ijms241612656.
Pathological mutations in leucine-rich repeat kinase 2 (LRRK2) gene are the major genetic cause of Parkinson's disease (PD). Multiple lines of evidence link LRRK2 to the control of vesicle dynamics through phosphorylation of a subset of RAB proteins. However, the molecular mechanisms underlying these processes are not fully elucidated. We have previously demonstrated that LRRK2 increases the exocyst complex assembly by Sec8 interaction, one of the eight members of the exocyst complex, and that Sec8 over-expression mitigates the LRRK2 pathological effect in PC12 cells. Here, we extend this analysis using LRRK2 drosophila models and show that the LRRK2-dependent exocyst complex assembly increase is downstream of RAB phosphorylation. Moreover, exocyst complex inhibition rescues mutant LRRK2 pathogenic phenotype in cellular and drosophila models. Finally, prolonged exocyst inhibition leads to a significant reduction in the LRRK2 protein level, overall supporting the role of the exocyst complex in the LRRK2 pathway. Taken together, our study suggests that modulation of the exocyst complex may represent a novel therapeutic target for PD.
富含亮氨酸重复激酶 2 (LRRK2) 基因的病理性突变是帕金森病 (PD) 的主要遗传原因。有多项证据表明，LRRK2 通过磷酸化 RAB 蛋白的亚类来控制囊泡动力学。然而，这些过程背后的分子机制尚未完全阐明。我们之前已经证明，LRRK2 通过与 Sec8 的相互作用增加了外泌体复合物的组装，Sec8 是外泌体复合物的八个成员之一，并且 Sec8 的过表达减轻了 PC12 细胞中 LRRK2 的病理性效应。在这里，我们使用 LRRK2 果蝇模型扩展了这一分析，并表明 RAB 磷酸化下游的 LRRK2 依赖的外泌体复合物组装增加。此外，外泌体复合物抑制可挽救细胞和果蝇模型中突变型 LRRK2 的致病表型。最后，长时间的外泌体抑制会导致 LRRK2 蛋白水平显著降低，这总体上支持了外泌体复合物在 LRRK2 通路中的作用。总之，我们的研究表明，外泌体复合物的调节可能代表 PD 的一个新的治疗靶点。
