PMID- 19878437 OWN - NLM STAT- MEDLINE DCOM- 20100205 LR - 20211203 IS - 1471-4159 (Electronic) IS - 0022-3042 (Linking) VI - 112 IP - 2 DP - 2010 Jan TI - A novel mTOR activating protein protects dopamine neurons against oxidative stress by repressing autophagy related cell death. PG - 366-76 LID - 10.1111/j.1471-4159.2009.06463.x [doi] AB - 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. FAU - Choi, Kyou-Chan AU - Choi KC AD - Division of Life and Pharmaceutical Sciences, College of Pharmacy, Brain Disease Research Institute, Ewha Woman's University, Seoul, South Korea. FAU - Kim, Shin-Hee AU - Kim SH FAU - Ha, Ji-Young AU - Ha JY FAU - Kim, Sang-Tae AU - Kim ST FAU - Son, Jin H AU - Son JH LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20091029 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Carrier Proteins) RN - 0 (Cell Cycle Proteins) RN - 0 (Eif4ebp1 protein, mouse) RN - 0 (Eukaryotic Initiation Factors) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Phosphoproteins) RN - 0 (RNA, Messenger) RN - 147336-22-9 (Green Fluorescent Proteins) RN - BBX060AN9V (Hydrogen Peroxide) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (Oxsr1 protein, rat) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - VTD58H1Z2X (Dopamine) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adaptor Proteins, Signal Transducing MH - Animals MH - Autophagy/drug effects/genetics/*physiology MH - Carrier Proteins/genetics/metabolism MH - Cell Cycle Proteins MH - Cell Line, Transformed MH - Cell Line, Tumor MH - Dopamine/*metabolism MH - Down-Regulation/drug effects/physiology MH - Eukaryotic Initiation Factors MH - Green Fluorescent Proteins/genetics MH - Hydrogen Peroxide/pharmacology MH - Intracellular Signaling Peptides and Proteins/*metabolism MH - Mice MH - Microscopy, Confocal/methods MH - Neuroblastoma MH - Neurons/drug effects/*physiology MH - Oxidative Stress/drug effects/*physiology MH - Phosphoproteins/genetics/metabolism MH - Phylogeny MH - Protein Kinases MH - Protein Serine-Threonine Kinases/genetics/*metabolism MH - RNA, Messenger/metabolism MH - Ribosomal Protein S6 Kinases, 70-kDa/genetics/metabolism MH - Signal Transduction/drug effects MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases MH - Transfection/methods EDAT- 2009/11/03 06:00 MHDA- 2010/02/06 06:00 CRDT- 2009/11/03 06:00 PHST- 2009/11/03 06:00 [entrez] PHST- 2009/11/03 06:00 [pubmed] PHST- 2010/02/06 06:00 [medline] AID - JNC6463 [pii] AID - 10.1111/j.1471-4159.2009.06463.x [doi] PST - ppublish SO - J Neurochem. 2010 Jan;112(2):366-76. doi: 10.1111/j.1471-4159.2009.06463.x. Epub 2009 Oct 29.