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A novel mTOR activating protein protects dopamine neurons against oxidative stress by repressing autophagy related cell death
Author(s) -
Choi KyouChan,
Kim ShinHee,
Ha JiYoung,
Kim SangTae,
Son Jin H.
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06463.x
Subject(s) - autophagy , pi3k/akt/mtor pathway , programmed cell death , microbiology and biotechnology , p70 s6 kinase 1 , protein kinase a , neuroprotection , dopamine , kinase , biology , mechanistic target of rapamycin , oxidative stress , chemistry , signal transduction , biochemistry , pharmacology , apoptosis , neuroscience
Our previous microarray analysis identified a neuroprotective protein Oxi‐α, 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‐α 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‐α is the first molecule discovered in dopamine neurons, which activates mTOR kinase. Indeed, the down‐regulation of Oxi‐α by OS suppresses the activation of mTOR kinase. The pathogenic effect of down‐regulated Oxi‐α 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.