Suppression of autophagy precipitates neuronal cell death following low doses of methamphetamine
Suppression of autophagy precipitates neuronal cell death following low doses of methamphetamine
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DOI：
10.1111/j.1471-4159.2008.05488.x
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发表时间：
2008-08-01
影响因子：
4.7
通讯作者：
Isidoro, Ciro
中科院分区：
文献类型：
--
作者：
Castino, Roberta;Lazzeri, Gloria;Isidoro, Ciro
滥用甲基苯丙胺对多巴胺能神经元有毒，导致黑质纹状体去神经和纹状体多巴胺损失。暴露于甲基苯丙胺后，黑质细胞体的数量通常保留，但其细胞质具有自噬样空泡化和α-突触核蛋白、泛素和parkin阳性包涵体的细胞质积累。自噬是否是附带现象，或者在甲基苯丙胺毒性机制中发挥作用，以及在后一种情况下，其作用是抵消还是促进神经毒性作用仍然不清楚。我们在甲基苯丙胺毒性的简单细胞模型中研究了信号通路和自噬激活的意义（保护性与毒性）以及自噬和泛素蛋白酶体通路在相同细胞内水平上的收敛。我们发现自噬响应甲基苯丙胺而迅速上调。共聚焦荧光显微镜和免疫电子显微镜研究表明，在暴露于甲基苯丙胺的细胞中，自噬溶酶体结构中存在α-突触核蛋白聚集体，这是一种与细胞存活相容的条件。通过药物或基因操纵 III 类磷脂酰肌醇 3 激酶介导的信号传导来抑制自噬，可阻止 α-突触核蛋白聚集体的去除，并促进 bax 介导的线粒体凋亡途径。
Methamphetamine abuse is toxic to dopaminergic neurons, causing nigrostriatal denervation and striatal dopamine loss. Following methamphetamine exposure, the number of nigral cell bodies is generally preserved, but their cytoplasm features autophagic-like vacuolization and cytoplasmic accumulation of alpha-synuclein-, ubiquitin- and parkin-positive inclusion-like bodies. Whether autophagy is epiphenomenal or it plays a role in the mechanism of methamphetamine toxicity and, in the latter case, whether its role consists of counteracting or promoting the neurotoxic effect remains obscure. We investigated the signaling pathway and the significance (protective vs. toxic) of autophagy activation and the convergence of the autophagic and the ubiquitin-proteasome pathways at the level of the same intracellular bodies in a simple cell model of methamphetamine toxicity. We show that autophagy is rapidly up-regulated in response to methamphetamine. Confocal fluorescence microscopy and immuno-electron microscopy studies demonstrated the presence of alpha-synuclein aggregates in autophagy-lysosomal structures in cells exposed to methamphetamine, a condition compatible with cell survival. Inhibition of autophagy either by pharmacologic or genetic manipulation of the class III Phosphatidylinositol-3 kinase-mediated signaling prevented the removal of alpha-synuclein aggregates and precipitated a bax-mediated mitochondrial apoptosis pathway.