Atp13a2 Deficiency Aggravates Astrocyte-Mediated Neuroinflammation via NLRP3 Inflammasome Activation
Atp13a2 Deficiency Aggravates Astrocyte-Mediated Neuroinflammation via NLRP3 Inflammasome Activation
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Atp13a2 缺陷通过 NLRP3 炎症小体激活加剧星形胶质细胞介导的神经炎症
DOI：
10.1111/cns.12514
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发表时间：
2016-06-01
影响因子：
5.5
通讯作者：
Hu, Gang
中科院分区：
文献类型：
--
作者：
Qiao, Chen;Yin, Nuo;Hu, Gang
目的：Atp13a2 (Park9) 基因编码跨膜溶酶体 P5 型 ATP 酶 (ATP13A2)，其错义或截短突变导致溶酶体功能障碍，从而导致帕金森病 (PD) 发病机制中的神经元死亡。然而，ATP13A2 在星形胶质细胞生物学特征中的作用，特别是在 PD 相关神经炎症的调节中的作用尚未得到研究。方法：我们培养了小鼠中脑的原代神经元和星形胶质细胞，以研究 1-甲基-4-苯基吡啶鎓 (MPP+) 治疗后星形胶质细胞 ATP13A2 调节溶酶体功能和神经炎症的机制。结果：我们发现星形胶质细胞表达相当水平的 ATP13A2，并且在星形胶质细胞诱导的强烈炎症中缺乏 ATP13A2，这加剧了暴露于 MPP+ 后的多巴胺能神经元损伤。值得注意的是，缺乏 ATP13A2 会增加溶酶体膜的通透性和组织蛋白酶 B 的释放，进而加剧 nod 样受体蛋白 3 (NLRP3) 炎性体的激活，从而从星形胶质细胞产生过量的 IL-1 β。此外，ATP13A2 的过度表达逆转了星形胶质细胞中 MPP+ 诱导的组织蛋白酶 B 释放和 NLRP3 炎性体激活。结论：我们的结果揭示了 ATP13A2 通过 NLRP3 炎症小体激活调节星形胶质细胞介导的神经炎症的新作用，从而揭示了 PD 病理模型中星形胶质细胞溶酶体与神经炎症之间的直接联系。
Aim: Atp13a2 (Park9) gene encodes a transmembrane lysosomal P5-type ATPase (ATP13A2), and its missense or truncation mutations leads to lysosomal dysfunction and consequently results in neuronal death in the pathogenesis of Parkinson's disease (PD). Nevertheless, the roles of ATP13A2 in the biological features of astrocytes, especially in the regulation of PD-related neuroinflammation, have not been investigated. Methods: We cultured primary neurons and astrocytes from mouse midbrain to investigate the mechanisms for astrocyte ATP13A2-regulated lysosomal function and neuroinflammation following 1-methyl-4-phenylpyridinium (MPP+) treatment. Results: We found that astrocytes expressed considerable levels of ATP13A2 and deficiency of ATP13A2 in astrocyte-induced intense inflammation, which exacerbated dopaminergic neuron damage after exposure to MPP+. Notably, lack of ATP13A2 increased lysosomal membrane permeabilization and cathepsin B release, which in turn exacerbated activation of nod-like receptor protein 3 (NLRP3) inflammasome to produce excess IL-1 beta from astrocytes. Furthermore, overexpression of ATP13A2 reversed MPP+-induced cathepsin B release and NLRP3 inflammasome activation in astrocytes. Conclusions: Our results have revealed a novel role of ATP13A2 in modulating astrocyte-mediated neuroinflammation via NLRP3 inflammasome activation, thus bringing to light of a direct link between astrocyte lysosome and neuroinflammation in the pathological model of PD.