Astrocyte-neuron communication through the complement C3-C3aR pathway in Parkinson’s disease

IF 8.8 2区 医学 Q1 IMMUNOLOGY Brain, Behavior, and Immunity Pub Date : 2024-09-15 DOI:10.1016/j.bbi.2024.09.022
Xiaosa Chi , Sijia Yin , Yadi Sun, Liang Kou, Wenkai Zou, Yiming Wang, Zongjie Jin, Tao Wang, Yun Xia
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Abstract

Neuroinflammation and autoimmunity are pivotal in the pathogenesis of neurodegenerative diseases. Complement activation and involvement of astrocyte-neuron C3/C3aR pathway have been observed, yet the mechanisms influencing α-synuclein (α-syn) pathology and neurodegeneration remain unclear. In this study, elevated levels of complement C3 were detected in the plasma of α-syn PFF-induced mice and the substantia nigra of A53T transgenic mice. Colocalization of complement C3 with astrocytes was also observed. Overexpression of complement C3 exacerbated motor dysfunction, dopaminergic neuron loss, and phosphorylated α-syn expression in mice injected with α-syn preformed fibrils (α-syn PFFs). Conversely, downregulation of complement C3 protected α-syn PFF-induced mice. Molecular investigations revealed that inhibition of Toll-like receptor 2 (TLR2) or NF-κB reduced complement C3 expression in primary astrocytes following α-syn PFF treatment. Astrocyte-neuron communication via the C3/C3aR pathway influenced α-syn PFF-induced neuronal apoptosis and α-syn pathology, potentially through modulation of GSK3β. These findings underscore the critical role of astrocyte-neuron communication via the C3/C3aR pathway in PD pathogenesis, highlighting its potential as a therapeutic target.

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帕金森病中通过补体 C3-C3aR 通路进行的星形胶质细胞-神经元交流。
神经炎症和自身免疫是神经退行性疾病发病机制中的关键因素。补体激活和星形胶质细胞-神经元 C3/C3aR 通路的参与已被观察到,但影响α-突触核蛋白(α-syn)病理和神经退行性变的机制仍不清楚。本研究在α-syn PFF诱导的小鼠血浆和A53T转基因小鼠黑质中检测到补体C3水平升高。还观察到补体 C3 与星形胶质细胞共定位。在注射了α-syn预成纤维(α-syn PFFs)的小鼠中,补体C3的过表达加剧了运动功能障碍、多巴胺能神经元的缺失和磷酸化α-syn的表达。相反,下调补体 C3 能保护α-syn PFF 诱导的小鼠。分子研究发现,抑制 Toll 样受体 2 (TLR2) 或 NF-κB 可减少原代星形胶质细胞在α-syn PFF 处理后的补体 C3 表达。通过 C3/C3aR 途径进行的星形胶质细胞-神经元交流影响了α-syn PFF 诱导的神经元凋亡和α-syn 病理学,可能是通过调节 GSK3β。这些发现强调了星形胶质细胞通过 C3/C3aR 通路与神经元交流在帕金森病发病机制中的关键作用,突出了其作为治疗靶点的潜力。
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来源期刊
CiteScore
29.60
自引率
2.00%
发文量
290
审稿时长
28 days
期刊介绍: Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.
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