Impairment of Atg5-Dependent Autophagic Flux Promotes Paraquat- and MPP-Induced Apoptosis But Not Rotenone or 6-Hydroxydopamine Toxicity

被引:54
作者
Garcia-Garcia, Aracely [1 ,2 ]
Anandhan, Annandurai [1 ,2 ]
Burns, Michaela [2 ]
Chen, Han [3 ]
Zhou, You [1 ,3 ]
Franco, Rodrigo [1 ,2 ]
机构
[1] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68583 USA
[2] Univ Nebraska, Sch Vet Med & Biomed Sci, Lincoln, NE 68583 USA
[3] Univ Nebraska, Ctr Biotechnol, Lincoln, NE 68583 USA
基金
美国国家卫生研究院;
关键词
autophagy; apoptosis; Atg5; cathepsins; paraquat; rotenone; MPP; 6-hydroxydopamine; neurodegeneration; Parkinsons disease; CELL-DEATH PATHWAYS; GROWTH-FACTOR PROTECTS; COMPLEX-I INHIBITORS; PARKINSONS-DISEASE; DOPAMINERGIC-NEURONS; ALPHA-SYNUCLEIN; SIGNALING PATHWAYS; OXIDATIVE STRESS; KINASE ACTIVATION; MAMMALIAN TARGET;
D O I
10.1093/toxsci/kft188
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Controversial reports on the role of autophagy as a survival or cell death mechanism in dopaminergic cell death induced by parkinsonian toxins exist. We investigated the alterations in autophagic flux and the role of autophagy protein 5 (Atg5)-dependent autophagy in dopaminergic cell death induced by parkinsonian toxins. Dopaminergic cell death induced by the mitochondrial complex I inhibitors 1-methyl-4-phenylpyridinium (MPP) and rotenone, the pesticide paraquat, and the dopamine analog 6-hydroxydopamine (6-OHDA) was paralleled by increased autophagosome accumulation. However, when compared with basal autophagy levels using chloroquine, autophagosome accumulation was a result of impaired autophagic flux. Only 6-OHDA induced an increase in autophagosome formation. Overexpression of a dominant negative form of Atg5 increased paraquat- and MPP-induced cell death. Stimulation of mammalian target of rapamycin (mTOR)-dependent signaling protected against cell death induced by paraquat, whereas MPP-induced toxicity was enhanced by wortmannin, a phosphoinositide 3-kinase class III inhibitor, rapamycin, and trehalose, an mTOR-independent autophagy activator. Modulation of autophagy by either pharmacological or genetic approaches had no effect on rotenone or 6-OHDA toxicity. Cell death induced by parkinsonian neurotoxins was inhibited by the pan caspase inhibitor (Z-VAD), but only caspase-3 inhibition was able to decrease MPP-induced cell death. Finally, inhibition of the lysosomal hydrolases, cathepsins, increased the toxicity by paraquat and MPP, supporting a protective role of Atg5-dependent autophagy and lysosomes degradation pathways on dopaminegic cell death. These results demonstrate that in dopaminergic cells, Atg5-dependent autophagy acts as a protective mechanism during apoptotic cell death induced by paraquat and MPP but not during rotenone or 6-OHDA toxicity.
引用
收藏
页码:166 / 182
页数:17
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