Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing
-
Animals
-
Autophagy / drug effects
-
Autophagy / genetics
-
Autophagy / physiology*
-
Carrier Proteins / genetics
-
Carrier Proteins / metabolism
-
Cell Cycle Proteins
-
Cell Line, Transformed
-
Cell Line, Tumor
-
Dopamine / metabolism*
-
Down-Regulation / drug effects
-
Down-Regulation / physiology
-
Eukaryotic Initiation Factors
-
Green Fluorescent Proteins / genetics
-
Hydrogen Peroxide / pharmacology
-
Intracellular Signaling Peptides and Proteins / metabolism*
-
Mice
-
Microscopy, Confocal / methods
-
Neuroblastoma
-
Neurons / drug effects
-
Neurons / physiology*
-
Oxidative Stress / drug effects
-
Oxidative Stress / physiology*
-
Phosphoproteins / genetics
-
Phosphoproteins / metabolism
-
Phylogeny
-
Protein Kinases
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / metabolism*
-
RNA, Messenger / metabolism
-
Ribosomal Protein S6 Kinases, 70-kDa / genetics
-
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
-
Signal Transduction / drug effects
-
Sirolimus / pharmacology
-
TOR Serine-Threonine Kinases
-
Transfection / methods
Substances
-
Adaptor Proteins, Signal Transducing
-
Carrier Proteins
-
Cell Cycle Proteins
-
Eif4ebp1 protein, mouse
-
Eukaryotic Initiation Factors
-
Intracellular Signaling Peptides and Proteins
-
Phosphoproteins
-
RNA, Messenger
-
Green Fluorescent Proteins
-
Hydrogen Peroxide
-
Protein Kinases
-
mTOR protein, mouse
-
mTOR protein, rat
-
Oxsr1 protein, rat
-
Protein Serine-Threonine Kinases
-
Ribosomal Protein S6 Kinases, 70-kDa
-
TOR Serine-Threonine Kinases
-
Dopamine
-
Sirolimus