The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson's disease

Astrocytes are essential cells of the central nervous system, characterized by dynamic relationships with neurons that range from functional metabolic interactions and regulation of neuronal firing activities, to the release of neurotrophic and neuroprotective factors. In Parkinson's disease (PD), dopaminergic neurons are a vulnerable population progressively lost during the course of the disease, but the effects of PD on astrocytes and astrocyte-to-neuron communication remains mostly unknown. This study focuses on the effects of the PD-related mutation LRRK2 G2019S in astrocytes, using patient-derived induced pluripotent stem cells. We report the alteration of extracellular vesicle (EV) biogenesis in astrocytes, and we identify the abnormal accumulation of key PD-related proteins within multi vesicular bodies (MVBs). We found that dopaminergic neurons internalize astrocyte-secreted EVs but LRRK2 G2019S EVs are abnormally enriched in the neurites and provide only marginal neurotrophic support to dopaminergic neurons. Thus, dysfunctional astrocyte-to-neuron communication via altered EV biological properties could participate in the progression of PD. Overall design: Differential gene expression between wild-type and LRRK2 G2019S iPSC-derived astrocytes.

星形胶质细胞（Astrocytes）是中枢神经系统的核心功能细胞，其与神经元间存在动态互作关系，涵盖功能代谢交互、神经元放电活动调控，以及神经营养与神经保护因子的分泌。在帕金森病（Parkinson's disease, PD）中，多巴胺能神经元作为易损群体随疾病进程进行性丢失，但PD对星形胶质细胞的影响以及星形胶质细胞-神经元通讯的相关机制目前尚不明晰。本研究以患者来源的诱导多能干细胞（induced pluripotent stem cells, iPSC）构建模型，聚焦PD相关突变LRRK2 G2019S对星形胶质细胞的作用。本研究证实星形胶质细胞的细胞外囊泡（extracellular vesicle, EV）生物发生过程出现异常，并发现关键PD相关蛋白在多囊泡体（multi vesicular bodies, MVBs）内发生异常蓄积。研究发现，多巴胺能神经元可摄取星形胶质细胞分泌的细胞外囊泡，但携带LRRK2 G2019S突变的囊泡在神经元突起中异常富集，且仅能为多巴胺能神经元提供极有限的神经营养支持。综上，由细胞外囊泡生物学特性异常所介导的功能异常星形胶质细胞-神经元通讯，可能参与帕金森病的疾病进展。
整体实验设计：野生型与LRRK2 G2019S突变iPSC来源星形胶质细胞的差异基因表达分析。