Autophagy Protects Against Aminochrome-Induced Cell Death in Substantia Nigra-Derived Cell Line

作者：Paris Irmgard; Munoz Patricia; Huenchuguala Sandro; Couve Eduardo; Sanders Laurie H; Greenamyre John Timothy; Caviedes Pablo; Segura Aguilar Juan^*

来源：Toxicological Sciences, 2011, 121(2): 376-388.

DOI：10.1093/toxsci/kfr060

• dopamine
• aminochrome
• autophagy
• apoptosis
• neurons
• DT-diaphorase

Aminochrome, the precursor of neuromelanin, has been proposed to be involved in the neurodegeneration neuromelanin-containing dopaminergic neurons in Parkinson's disease. We aimed to study the mechanism of aminochrome-dependent cell death in a cell line derived from rat substantia nigra. We found that aminochrome (50 mu M), in the presence of NAD(P)H-quinone oxidoreductase, EC 1.6.99.2 (DT)-diaphorase inhibitor dicoumarol (DIC) (100 mu M), induces significant cell death (62 +/- 3%; p < 0.01), increase in caspase-3 activation (p < 0.001), release of cytochrome C, disruption of mitochondrial membrane potential (p < 0.01), damage of mitochondrial DNA, damage of mitochondria determined with transmission electron microscopy, a dramatic morphological change characterized as cell shrinkage, and significant increase in number of autophagic vacuoles. To determine the role of autophagy on aminochrome-induced cell death, we incubated the cells in the presence of vinblastine and rapamycin. Interestingly, 10 mu M vinblastine induces a 5.9-fold (p < 0.001) and twofold (p < 0.01) significant increase in cell death when the cells were incubated with 30 mu M aminochrome in the absence and presence of DIC, respectively, whereas 10 mu M rapamycin preincubated 24 h before addition of 50 mu M aminochrome in the absence and the presence of 100 mu M DIC induces a significant decrease (p < 0.001) in cell death. In conclusion, autophagy seems to be an important protective mechanism against two different aminochrome-induced cell deaths that initially showed apoptotic features. The cell death induced by aminochrome when DT-diaphorase is inhibited requires activation of mitochondrial pathway, whereas the cell death induced by aminochrome alone requires inhibition of autophagy-dependent degrading of damaged organdies and recycling through lysosomes.

• 出版日期2011-6