-Opioid Receptor Activation Attenuates the Oligomer Formation Induced by Hypoxia and/or -Synuclein Overexpression/Mutation Through Dual Signaling Pathways

We have recently demonstrated that -opioid receptor (DOR) activation attenuates -synuclein expression/aggregation induced by MPP(+) and/or severe hypoxia. Since -synuclein plays a critical role in the pathogenesis of Parkinson's disease, DOR activation may trigger an antiparkinson pathway(s) against -synuclein-induced injury. However, the underlying mechanism is unknown yet. In HEK293T and PC12 cells, we investigated the effects of DOR activation on the oligomer formation induced by -synuclein overexpression and mutation in normoxic and hypoxic conditions and explored the potential signaling pathways for DOR protection. We found that (1) increased expression of both wild-type and A53T-mutant -synuclein led to the formation of -synuclein oligomers and cytotoxic injury; (2) DOR activation largely attenuated the formation of toxic -synuclein oligomers induced by -synuclein overexpression/mutation and/or hypoxia; (3) DOR activation attenuated -synuclein-induced cytotoxicity through TORC1/SIK1/CREB, but not the phospho-CREB pathway, while DOR activation reduced hypoxic cell injury through the phospho-CREB mechanism; and (4) the interaction of -synuclein and the DJ-1 was involved in the mechanisms for DOR-mediated protection against -synuclein oligomer formation. Our findings suggest that DOR attenuates the formation of toxic -synuclein oligomers through the phos-CREB pathway under hypoxic conditions, and through TORC1/SIK1/CREB pathways in the conditions of -synuclein overexpression and mutation. The DJ-1 gene was involved in the DOR protection against parkinsonian injury.