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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.
Mol Neurobiol. 2019 May; 56(5):3463-3475.MN

Abstract

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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Authors+Show Affiliations

Chen T
Department of Neurology, Hainan General Hospital, Haikou, Hainan, China. The University of Texas McGovern Medical School, Houston, TX, USA.
Wang Q
The University of Texas McGovern Medical School, Houston, TX, USA.
Chao D
The University of Texas McGovern Medical School, Houston, TX, USA.
Xia TC
The University of Texas McGovern Medical School, Houston, TX, USA. The University of Connecticut, Storrs, CT, USA.
Sheng S
The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
Li ZR
Department of Neurology, Hainan General Hospital, Haikou, Hainan, China.
Zhao JN
Department of Neurology, Hainan General Hospital, Haikou, Hainan, China.
Wen GQ
Department of Neurology, Hainan General Hospital, Haikou, Hainan, China.
Ding G
Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China.
Xia Y
The University of Texas McGovern Medical School, Houston, TX, USA. Y55738088@gmail.com. Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China. Y55738088@gmail.com. Department of Aeronautics and Astronautics, Fudan University, Shanghai, China. Y55738088@gmail.com.

MeSH

AnimalsBenzimidazolesCell HypoxiaCell SurvivalCyclic AMP Response Element-Binding ProteinHEK293 CellsHumansModels, BiologicalMutant ProteinsMutationOligopeptidesPC12 CellsPhosphorylationProtein Deglycase DJ-1Protein MultimerizationProtein Serine-Threonine KinasesRatsReceptors, Opioid, deltaSerineSignal Transductionalpha-Synuclein

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30132200

Citation

Chen, Tao, et al. "Δ-Opioid Receptor Activation Attenuates the Oligomer Formation Induced By Hypoxia And/or α-Synuclein Overexpression/Mutation Through Dual Signaling Pathways." Molecular Neurobiology, vol. 56, no. 5, 2019, pp. 3463-3475.
Chen T, Wang Q, Chao D, et al. Δ-Opioid Receptor Activation Attenuates the Oligomer Formation Induced by Hypoxia and/or α-Synuclein Overexpression/Mutation Through Dual Signaling Pathways. Mol Neurobiol. 2019;56(5):3463-3475.
Chen, T., Wang, Q., Chao, D., Xia, T. C., Sheng, S., Li, Z. R., Zhao, J. N., Wen, G. Q., Ding, G., & Xia, Y. (2019). Δ-Opioid Receptor Activation Attenuates the Oligomer Formation Induced by Hypoxia and/or α-Synuclein Overexpression/Mutation Through Dual Signaling Pathways. Molecular Neurobiology, 56(5), 3463-3475. https://doi.org/10.1007/s12035-018-1316-1
Chen T, et al. Δ-Opioid Receptor Activation Attenuates the Oligomer Formation Induced By Hypoxia And/or α-Synuclein Overexpression/Mutation Through Dual Signaling Pathways. Mol Neurobiol. 2019;56(5):3463-3475. PubMed PMID: 30132200.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - δ-Opioid Receptor Activation Attenuates the Oligomer Formation Induced by Hypoxia and/or α-Synuclein Overexpression/Mutation Through Dual Signaling Pathways. AU - Chen,Tao, AU - Wang,Qinyu, AU - Chao,Dongman, AU - Xia,Terry C, AU - Sheng,Shiying, AU - Li,Zhuo-Ri, AU - Zhao,Jian-Nong, AU - Wen,Guo-Qiang, AU - Ding,Guanghong, AU - Xia,Ying, Y1 - 2018/08/21/ PY - 2018/05/04/received PY - 2018/08/13/accepted PY - 2018/8/23/pubmed PY - 2019/8/14/medline PY - 2018/8/23/entrez KW - CREB KW - Cytoprotection KW - DJ-1 KW - Hypoxia KW - Oligomer formation KW - Parkinson’s disease KW - TORC1 KW - α-Synuclein KW - δ-Opioid receptor SP - 3463 EP - 3475 JF - Molecular neurobiology JO - Mol Neurobiol VL - 56 IS - 5 N2 - 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. SN - 1559-1182 UR - https://www.unboundmedicine.com/medline/citation/30132200/δ_Opioid_Receptor_Activation_Attenuates_the_Oligomer_Formation_Induced_by_Hypoxia_and/or_α_Synuclein_Overexpression/Mutation_Through_Dual_Signaling_Pathways_ DB - PRIME DP - Unbound Medicine ER -