Department of Anatomy, School of Medicine, Konkuk University, Seoul 143-701, Korea .
J Biol Chem. 2010 Mar 19;285(12):9262-72. doi: 10.1074/jbc.M109.081125. Epub 2010 Jan 13.
Abnormal neuronal aggregation of alpha-synuclein is implicated in the development of many neurological disorders, including Parkinson disease and dementia with Lewy bodies. Glial cells also show extensive alpha-synuclein pathology and may contribute to disease progression. However, the mechanism that produces the glial alpha-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that alpha-synuclein proteins released from neuronal cells are taken up by astrocytes through endocytosis and form inclusion bodies. The glial accumulation of alpha-synuclein through the transmission of the neuronal protein was also demonstrated in a transgenic mouse model expressing human alpha-synuclein. Furthermore, astrocytes that were exposed to neuronal alpha-synuclein underwent changes in the gene expression profile reflecting an inflammatory response. Induction of pro-inflammatory cytokines and chemokines correlated with the extent of glial accumulation of alpha-synuclein. Together, these results suggest that astroglial alpha-synuclein pathology is produced by direct transmission of neuronal alpha-synuclein aggregates, causing inflammatory responses. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target.
异常的α-突触核蛋白神经元聚集与许多神经退行性疾病的发展有关，包括帕金森病和路易体痴呆。神经胶质细胞也显示出广泛的α-突触核蛋白病理学，并可能有助于疾病的进展。然而，产生神经胶质α-突触核蛋白病理学的机制以及神经元和胶质细胞在疾病侵袭的微环境中的相互作用仍然未知。在这里，我们表明，神经元细胞释放的α-突触核蛋白蛋白通过内吞作用被星形胶质细胞摄取，并形成包含体。在表达人α-突触核蛋白的转基因小鼠模型中，也证明了通过神经元蛋白的传递导致α-突触核蛋白在神经胶质细胞中的积累。此外，暴露于神经元α-突触核蛋白的星形胶质细胞经历了反映炎症反应的基因表达谱的变化。促炎细胞因子和趋化因子的诱导与α-突触核蛋白在神经胶质细胞中的积累程度相关。总之，这些结果表明，星形胶质细胞α-突触核蛋白病理学是由神经元α-突触核蛋白聚集物的直接传递产生的，引起炎症反应。因此，这个传递步骤是致病性神经胶质反应的一个重要介质，并可能成为一个新的治疗靶点。
