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

  • Chen, Tao1, 2
  • Wang, Qinyu2
  • Chao, Dongman2
  • Xia, Terry C.2, 3
  • Sheng, Shiying4
  • Li, Zhuo-Ri1
  • Zhao, Jian-Nong1
  • Wen, Guo-Qiang1
  • Ding, Guanghong5
  • Xia, Ying2, 5, 6
  • 1 Hainan General Hospital, Department of Neurology, Haikou, Hainan, China , Haikou (China)
  • 2 The University of Texas McGovern Medical School, Houston, TX, USA , Houston (United States)
  • 3 The University of Connecticut, Storrs, CT, USA , Storrs (United States)
  • 4 The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China , Changzhou (China)
  • 5 Fudan University, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Shanghai, China , Shanghai (China)
  • 6 Fudan University, Department of Aeronautics and Astronautics, Shanghai, China , Shanghai (China)
Published Article
Molecular Neurobiology
Springer US
Publication Date
Aug 21, 2018
DOI: 10.1007/s12035-018-1316-1
Springer Nature


We have recently demonstrated that δ-opioid receptor (DOR) activation attenuates α-synuclein expression/aggregation induced by MPP(+) and/or severe hypoxia. Since α-synuclein plays a critical role in the pathogenesis of Parkinson’s disease, DOR activation may trigger an antiparkinson pathway(s) against α-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 α-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 α-synuclein led to the formation of α-synuclein oligomers and cytotoxic injury; (2) DOR activation largely attenuated the formation of toxic α-synuclein oligomers induced by α-synuclein overexpression/mutation and/or hypoxia; (3) DOR activation attenuated α-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 α-synuclein and the DJ-1 was involved in the mechanisms for DOR-mediated protection against α-synuclein oligomer formation. Our findings suggest that DOR attenuates the formation of toxic α-synuclein oligomers through the phos-CREB pathway under hypoxic conditions, and through TORC1/SIK1/CREB pathways in the conditions of α-synuclein overexpression and mutation. The DJ-1 gene was involved in the DOR protection against parkinsonian injury.

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