The ER chaperone sigma-1 receptor stabilizes and increases the phosphoryaltion and translocation of Nrf2 to elicit cellular responses against ROS-induced neurodegeneration

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NIDA	OXIDSTRESS-5

Authors

• S.A. Wang
• S.Y. Yi
• T.P. Su

Abstract

The central nervous system is endowed with an antioxidant defense mechanism consisting of enzymes whose genes are tightly controlled by the antioxidant response element in the promoter activated by nuclear factor E2-related factor 2. We hypothesized here that Sig-1R chaperones at the ER may attenuate the oxidative stress by regulating the stabilization and activation of Nrf-2. In subcellular fractionations, we found that Nrf-2 is in fact enriched in the ER and nuclear fractions and is present only in minimal amount in the cytoplasm. Importantly, Nrf-2 is found to co-immunoprecipiate with Sig-1Rs. When neurons are treated with cycloheximide to examine for newly synthesized Nrf-2, we found that the Nrf-2 stability is largely decreased. Nrf-2 phosphorylation is essential for its activation. We found that Sig-1R agonists cause an increase of phosphorylated Nrf-2 in the brain and that the Sig-1R antagonist blocks this effect. The phosphorylated Nrf-2 exists mainly in the nucleus. In alignment with the downstream target of Nrf-2 gene regulation, the mRNA of one of Nrf-2-targeted genes the heme-oxygenase-1 is reduced in Sig-1R knockdown neurons. Correspondingly, the HO-1 mRNA is increased by Sig-1R agonists whose action in this regard is blocked by Sig-1R antagonist.

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