Astrocytes Protect Human Dopaminergic Neurons from α-Synuclein Accumulation and Propagation
Astrocytes Protect Human Dopaminergic Neurons from α-Synuclein Accumulation and Propagation
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DOI：
10.1523/jneurosci.0954-20.2020
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发表时间：
2020-11-04
影响因子：
5.3
通讯作者：
Krainc, Dimitri
中科院分区：
文献类型：
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作者：
Tsunemi, Taiji;Ishiguro, Yuta;Krainc, Dimitri
帕金森病的病理标志是含有α-突触核蛋白的路易体/神经突几乎仅在神经元中积累，而很少在神经胶质细胞中积累。然而，新出现的证据表明，神经胶质细胞如星形胶质细胞在α-突触核蛋白病理学的发展中起重要作用。使用来自健康受试者和携带溶酶体ATP 13 A2突变（一种单基因形式的突触核蛋白病）的患者的诱导多能干细胞衍生的多巴胺能神经元和星形胶质细胞，我们发现星形胶质细胞迅速内化α-突触核蛋白，并且与神经元相比表现出更高的溶酶体降解速率。此外，共培养星形胶质细胞和神经元导致神经元中α-突触核蛋白的积累减少，从而减少了α-突触核蛋白的神经元间转移。星形胶质细胞的这些保护功能被ATP 13 A2缺陷减弱，表明星形胶质细胞中ATP 13 A2功能的丧失至少部分地导致神经元α-突触核蛋白病理学。总之，我们的研究结果强调了星形胶质细胞中溶酶体功能在突触核蛋白病发病机制中的重要性。
The pathologic hallmark of Parkinson's disease is the accumulation of alpha-synuclein-containing Lewy bodies/neurites almost exclusively in neurons, and rarely in glial cells. However, emerging evidence suggests that glia such as astrocytes play an important role in the development of alpha-synuclein pathology. Using induced pluripotent stem-derived dopaminergic neurons and astrocytes from healthy subjects and patients carrying mutations in lysosomal ATP13A2, a monogenic form of synucleinopathy, we found that astrocytes rapidly internalized alpha-synuclein, and exhibited higher lysosomal degradation rates compared with neurons. Moreover, coculturing astrocytes and neurons led to decreased accumulation of alpha-synuclein in neurons and consequently diminished interneuronal transfer of alpha-synuclein. These protective functions of astrocytes were attenuated by ATP13A2 deficiency, suggesting that the loss of ATP13A2 function in astrocytes at least partially contributes to neuronal alpha-synuclein pathology. Together, our results highlight the importance of lysosomal function in astrocytes in the pathogenesis of synucleinopathies.