A novel mTOR activating protein protects dopamine neurons against oxidative stress by repressing autophagy related cell death.
Our previous microarray analysis identified a neuroprotective protein Oxi-alpha, that was down-regulated during oxidative stress (OS)-induced cell death in dopamine neurons [Neurochem. Res. (2004) vol. 29, pp. 1223]. Here we find that the phylogenetically conserved Oxi-alpha protects against OS by a novel mechanism: activation of the mammalian target of rapamycin (mTOR) kinase and subsequent repression of autophagic vacuole accumulation and cell death. To the best of our knowledge, Oxi-alpha is the first molecule discovered in dopamine neurons, which activates mTOR kinase. Indeed, the down-regulation of Oxi-alpha by OS suppresses the activation of mTOR kinase. The pathogenic effect of down-regulated Oxi-alpha was confirmed by gene-specific knockdown experiment, which resulted in not only the repression of mTOR kinase and the subsequent phosphorylation of p70 S6 kinase and 4E-BP1, but also enhanced susceptibility to OS. In accordance with these observations, treatment with rapamycin, an mTOR inhibitor and autophagy inducer, potentiated OS-induced cell death, while similar treatment with an autophagy inhibitor, 3-methyladenine protected the dopamine cells. Our findings present evidence for the presence of a novel class of molecule involved in autophagic cell death triggered by OS in dopamine neurons.
Choi
Kyou-Chan
KC
Division of Life and Pharmaceutical Sciences, College of Pharmacy, Brain Disease Research Institute, Ewha Woman's University, Seoul, South Korea.
Kim
Shin-Hee
SH
Ha
Ji-Young
JY
Kim
Sang-Tae
ST
Son
Jin H
JH
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D039642:Eukaryotic Initiation Factors; D049452:Green Fluorescent Proteins / Q000235:genetics; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal / Q000379:methods; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014162:Transfection / Q000379:methods
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D006861:Hydrogen Peroxide; D011494:Protein Kinases; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; C506604:Oxsr1 protein, rat; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D004298:Dopamine; D020123:Sirolimus