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δ-Opioid Receptor Activation Attenuates Hypoxia/MPP+-Induced Downregulation of PINK1: a Novel Mechanism of Neuroprotection Against Parkinsonian Injury

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Abstract

There is emerging evidence suggesting that neurotoxic insults and hypoxic/ischemic injury are underlying causes of Parkinson’s disease (PD). Since PTEN-induced kinase 1 (PINK1) dysfunction is involved in the molecular genesis of PD and since our recent studies have demonstrated that the δ-opioid receptor (DOR) induced neuroprotection against hypoxic and 1-methyl-4-phenyl-pyridimium (MPP+) insults, we sought to explore whether DOR protects neuronal cells from hypoxic and/or MPP+ injury via the regulation of PINK1-related pathways. Using highly differentiated rat PC12 cells exposed to either severe hypoxia (0.5–1% O2) for 24–48 h or varying concentrations of MPP+, we found that both hypoxic and MPP+ stress reduced the level of PINK1 expression, while incubation with the specific DOR agonist UFP-512 reversed this reduction and protected the cells from hypoxia and/or MPP+-induced injury. However, the DOR-mediated cytoprotection largely disappeared after knocking down PINK1 by PINK1 small interfering RNA. Moreover, we examined several important signaling molecules related to cell survival and apoptosis and found that DOR activation attenuated the hypoxic and/or MPP+-induced reduction in phosphorylated Akt and inhibited the activation of cleaved caspase-3, whereas PINK1 knockdown largely deprived the cell of the DOR-induced effects. Our novel data suggests a unique mechanism underlying DOR-mediated cytoprotection against hypoxic and MPP+ stress via a PINK1-mediated regulation of signaling.

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References

  1. GBD 2013 Mortality and Causes of Death Collaborators (2015) Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385(9963):117–171. https://doi.org/10.1016/S0140-6736(14)61682-2

    Article  Google Scholar 

  2. Shulman JM, De Jager PL, Feany MB (2011) Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol 6:193–222. https://doi.org/10.1146/annurev-pathol-011110-130242

    Article  CAS  PubMed  Google Scholar 

  3. Sveinbjornsdottir S (2016) The clinical symptoms of Parkinson’s disease. J Neurochem 139(Suppl 1):318–324. https://doi.org/10.1111/jnc.13691

    Article  CAS  PubMed  Google Scholar 

  4. Kazlauskaite A, Muqit MM (2015) PINK1 and Parkin—mitochondrial interplay between phosphorylation and ubiquitylation in Parkinson’s disease. FEBS J 282(2):215–223. https://doi.org/10.1111/febs.13127

    Article  CAS  PubMed  Google Scholar 

  5. Haddad D, Nakamura K (2015) Understanding the susceptibility of dopamine neurons to mitochondrial stressors in Parkinson’s disease. FEBS Lett 589(24 Pt A):3702–3713. https://doi.org/10.1016/j.febslet.2015.10.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pickrell AM, Youle RJ (2015) The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 85(2):257–273. https://doi.org/10.1016/j.neuron.2014.12.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gautier CA, Corti O, Brice A (2014) Mitochondrial dysfunctions in Parkinson’s disease. Rev Neurol 170(5):339–343. https://doi.org/10.1016/j.neurol.2013.06.003

    Article  CAS  PubMed  Google Scholar 

  8. Luo Y, Hoffer A, Hoffer B, Qi X (2015) Mitochondria: a therapeutic target for Parkinson’s disease? Int J Mol Sci 16(9):20704–20730. https://doi.org/10.3390/ijms160920704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cagin U, Duncan OF, Gatt AP, Dionne MS, Sweeney ST, Bateman JM (2015) Mitochondrial retrograde signaling regulates neuronal function. Proc Natl Acad Sci U S A 112(44):E6000–E6009. https://doi.org/10.1073/pnas.1505036112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Monroy-Jaramillo N, Guerrero-Camacho JL, Rodriguez-Violante M, Boll-Woehrlen MC, Yescas-Gomez P, Alonso-Vilatela ME, Lopez-Lopez M (2014) Genetic mutations in early-onset Parkinson’s disease Mexican patients: molecular testing implications. Am J Med Genet B Neuropsychiatr Genet 165B(3):235–244. https://doi.org/10.1002/ajmg.b.32228

    Article  CAS  PubMed  Google Scholar 

  11. Pridgeon JW, Olzmann JA, Chin LS, Li L (2007) PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 5(7):e172. https://doi.org/10.1371/journal.pbio.0050172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wu W, Xu H, Wang Z, Mao Y, Yuan L, Luo W, Cui Z, Cui T et al (2015) PINK1-Parkin-mediated mitophagy protects mitochondrial integrity and prevents metabolic stress-induced endothelial injury. PLoS One 10(7):e0132499. https://doi.org/10.1371/journal.pone.0132499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dai H, Deng Y, Zhang J, Han H, Zhao M, Li Y, Zhang C, Tian J et al (2015) PINK1/Parkin-mediated mitophagy alleviates chlorpyrifos-induced apoptosis in SH-SY5Y cells. Toxicology 334:72–80. https://doi.org/10.1016/j.tox.2015.06.003

    Article  CAS  PubMed  Google Scholar 

  14. Eiyama A, Okamoto K (2015) PINK1/Parkin-mediated mitophagy in mammalian cells. Curr Opin Cell Biol 33:95–101. https://doi.org/10.1016/j.ceb.2015.01.002

    Article  CAS  PubMed  Google Scholar 

  15. Kitada T, Tong Y, Gautier CA, Shen J (2009) Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice. J Neurochem 111(3):696–702. https://doi.org/10.1111/j.1471-4159.2009.06350.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, Martella G, Bonsi P, Zhang C et al (2007) Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci U S A 104(27):11441–11446. https://doi.org/10.1073/pnas.0702717104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ryan BJ, Hoek S, Fon EA, Wade-Martins R (2015) Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem Sci 40(4):200–210. https://doi.org/10.1016/j.tibs.2015.02.003

    Article  CAS  PubMed  Google Scholar 

  18. Chao D, Xia Y (2010) Ionic storm in hypoxic/ischemic stress: can opioid receptors subside it? Prog Neurobiol 90(4):439–470. https://doi.org/10.1016/j.pneurobio.2009.12.007

    Article  CAS  PubMed  Google Scholar 

  19. Sen D, Huchital M, Chen YL (2013) Crosstalk between delta opioid receptor and nerve growth factor signaling modulates neuroprotection and differentiation in rodent cell models. Int J Mol Sci 14(10):21114–21139. https://doi.org/10.3390/ijms141021114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen T, Li J, Chao D, Sandhu HK, Liao X, Zhao J, Wen G, Xia Y (2014) Delta-opioid receptor activation reduces alpha-synuclein overexpression and oligomer formation induced by MPP(+) and/or hypoxia. Exp Neurol 255:127–136. https://doi.org/10.1016/j.expneurol.2014.02.022

    Article  CAS  PubMed  Google Scholar 

  21. Xu Y, Zhi F, Shao N, Wang R, Yang Y, Xia Y (2016) Cytoprotection against hypoxic and/or MPP(+) injury: effect of delta-opioid receptor activation on caspase 3. Int J Mol Sci 17(8):1179. https://doi.org/10.3390/ijms17081179

    Article  CAS  PubMed Central  Google Scholar 

  22. Chao D, Wang Q, Balboni G, Ding G, Xia Y (2016) Attenuating ischemic disruption of K(+) homeostasis in the cortex of hypoxic-ischemic neonatal rats: DOR activation vs. acupuncture treatment. Mol Neurobiol 53(10):7213–7227. https://doi.org/10.1007/s12035-015-9621-4

    Article  CAS  PubMed  Google Scholar 

  23. Borlongan C, Su T, Wang Y (2000) Treatment with delta opioid peptide enhances in vitro and in vivo survival of rat dopaminergic neurons. Neuroreport 11(5):923–926

    Article  CAS  PubMed  Google Scholar 

  24. Borlongan C, Su T, Wang Y (2001) Delta opioid peptide augments functional effects and intrastriatal graft survival of rat fetal ventral mesencephalic cells. Cell Transplant 10(1):53–58

    Article  CAS  PubMed  Google Scholar 

  25. Zhao P, Huang Y, Zuo Z (2006) Opioid preconditioning induces opioid receptor-dependent delayed neuroprotection against ischemia in rats. J Neuropathol Exp Neurol 65(10):945–952

    Article  CAS  PubMed  Google Scholar 

  26. Chiao S, Zuo Z (2014) A double-edged sword: volatile anesthetic effects on the neonatal brain. Brain Sci 4(2):273–294

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chao D, Bazzy-Asaad A, Balboni G, Xia Y (2007) Delta-, but not mu-, opioid receptor stabilizes K(+) homeostasis by reducing Ca(2+) influx in the cortex during acute hypoxia. J Cell Physiol 212(1):60–67. https://doi.org/10.1002/jcp.21000

    Article  CAS  PubMed  Google Scholar 

  28. Ma MC, Qian H, Ghassemi F, Zhao P, Xia Y (2005) Oxygen-sensitive {delta}-opioid receptor-regulated survival and death signals: novel insights into neuronal preconditioning and protection. J Biol Chem 280(16):16208–16218. https://doi.org/10.1074/jbc.M408055200

    Article  CAS  PubMed  Google Scholar 

  29. Zhang J, Gibney GT, Zhao P, Xia Y (2002) Neuroprotective role of delta-opioid receptors in cortical neurons. Am J Physiol Cell Physiol 282(6):C1225–C1234. https://doi.org/10.1152/ajpcell.00226.2001

    Article  CAS  PubMed  Google Scholar 

  30. Saberzadeh J, Arabsolghar R, Takhshid MA (2016) Alpha synuclein protein is involved in aluminum-induced cell death and oxidative stress in PC12 cells. Brain Res 1635:153–160. https://doi.org/10.1016/j.brainres.2016.01.037

    Article  CAS  PubMed  Google Scholar 

  31. Park HJ, Zhao TT, Lee KS, Lee SH, Shin KS, Park KH, Choi HS, Lee MK (2015) Effects of (-)-sesamin on 6-hydroxydopamine-induced neurotoxicity in PC12 cells and dopaminergic neuronal cells of Parkinson’s disease rat models. Neurochem Int 83-84:19–27. https://doi.org/10.1016/j.neuint.2015.01.003

    Article  CAS  PubMed  Google Scholar 

  32. Maioli M, Rinaldi S, Migheli R, Pigliaru G, Rocchitta G, Santaniello S, Basoli V, Castagna A et al (2015) Neurological morphofunctional differentiation induced by REAC technology in PC12. A neuro protective model for Parkinson’s disease. Sci Rep 5:10439. https://doi.org/10.1038/srep10439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shafer TJ, Atchison WD (1991) Transmitter, ion channel and receptor properties of pheochromocytoma (PC12) cells: a model for neurotoxicological studies. Neurotoxicology 12(3):473–492

    CAS  PubMed  Google Scholar 

  34. Abeliovich A (2014) Neurological disorders: quality-control pathway unlocked. Nature 510(7503):44–45. https://doi.org/10.1038/510044a

    Article  CAS  PubMed  Google Scholar 

  35. Wilhelmus MM, Nijland PG, Drukarch B, de Vries HE, van Horssen J (2012) Involvement and interplay of Parkin, PINK1, and DJ1 in neurodegenerative and neuroinflammatory disorders. Free Radic Biol Med 53(4):983–992. https://doi.org/10.1016/j.freeradbiomed.2012.05.040

    Article  CAS  PubMed  Google Scholar 

  36. Abeliovich A (2010) Parkinson’s disease: mitochondrial damage control. Nature 463(7282):744–745. https://doi.org/10.1038/463744a

    Article  CAS  PubMed  Google Scholar 

  37. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787–795. https://doi.org/10.1038/nature05292

    Article  CAS  PubMed  Google Scholar 

  38. Wei X, Gao H, Zou J, Liu X, Chen D, Liao J, Xu Y, Ma L et al (2016) Contra-directional coupling of Nur77 and Nurr1 in neurodegeneration: a novel mechanism for memantine-induced anti-inflammation and anti-mitochondrial impairment. Mol Neurobiol 53(9):5876–5892. https://doi.org/10.1007/s12035-015-9477-7

    Article  CAS  PubMed  Google Scholar 

  39. Ordureau A, Heo JM, Duda DM, Paulo JA, Olszewski JL, Yanishevski D, Rinehart J, Schulman BA et al (2015) Defining roles of PARKIN and ubiquitin phosphorylation by PINK1 in mitochondrial quality control using a ubiquitin replacement strategy. Proc Natl Acad Sci U S A 112(21):6637–6642. https://doi.org/10.1073/pnas.1506593112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ramsay RR, Singer TP (1986) Energy-dependent uptake of N-methyl-4-phenylpyridinium, the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, by mitochondria. J Biol Chem 261(17):7585–7587

    CAS  PubMed  Google Scholar 

  41. Venderova K, Park DS (2012) Programmed cell death in Parkinson’s disease. Cold Spring Harb Perspect Med 2(8):a009365. https://doi.org/10.1101/cshperspect.a009365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Aksenov V, Long J, Liu J, Szechtman H, Khanna P, Matravadia S, Rollo CD (2013) A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice. Age 35(1):23–33. https://doi.org/10.1007/s11357-011-9325-2

    Article  CAS  PubMed  Google Scholar 

  43. Nagase M, Takahashi Y, Watabe AM, Kubo Y, Kato F (2014) On-site energy supply at synapses through monocarboxylate transporters maintains excitatory synaptic transmission. J Neurosci 34(7):2605–2617. https://doi.org/10.1523/JNEUROSCI.4687-12.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gao J, Zhu ZR, Ding HQ, Qian Z, Zhu L, Ke Y (2007) Vulnerability of neurons with mitochondrial dysfunction to oxidative stress is associated with down-regulation of thioredoxin. Neurochem Int 50(2):379–385. https://doi.org/10.1016/j.neuint.2006.09.007

    Article  CAS  PubMed  Google Scholar 

  45. Devireddy S, Liu A, Lampe T, Hollenbeck PJ (2015) The organization of mitochondrial quality control and life cycle in the nervous system in vivo in the absence of PINK1. J Neurosci 35(25):9391–9401. https://doi.org/10.1523/JNEUROSCI.1198-15.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sanchez-Mora RM, Arboleda H, Arboleda G (2012) PINK1 overexpression protects against C2-ceramide-induced CAD cell death through the PI3K/AKT pathway. J Mol Neurosci 47(3):582–594. https://doi.org/10.1007/s12031-011-9687-z

    Article  CAS  PubMed  Google Scholar 

  47. Dagda RK, Chu CT (2009) Mitochondrial quality control: insights on how Parkinson’s disease related genes PINK1, parkin, and Omi/HtrA2 interact to maintain mitochondrial homeostasis. J Bioenerg Biomembr 41(6):473–479. https://doi.org/10.1007/s10863-009-9255-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Heeman B, Van den Haute C, Aelvoet SA, Valsecchi F, Rodenburg RJ, Reumers V, Debyser Z, Callewaert G et al (2011) Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy maintenance. J Cell Sci 124(Pt 7):1115–1125. https://doi.org/10.1242/jcs.078303

    Article  CAS  PubMed  Google Scholar 

  49. Koyano F, Matsuda N (2015) Molecular mechanisms underlying PINK1 and Parkin catalyzed ubiquitylation of substrates on damaged mitochondria. Biochim Biophys Acta 1853(10 Pt B):2791–2796. https://doi.org/10.1016/j.bbamcr.2015.02.009

    Article  CAS  PubMed  Google Scholar 

  50. Yang X, Wei A, Liu Y, He G, Zhou Z, Yu Z (2013) IGF-1 protects retinal ganglion cells from hypoxia-induced apoptosis by activating the Erk-1/2 and Akt pathways. Mol Vis 19:1901–1912

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Stegeman H, Span PN, Peeters WJ, Verheijen MM, Grenman R, Meijer TW, Kaanders JH, Bussink J (2016) Interaction between hypoxia, AKT and HIF-1 signaling in HNSCC and NSCLC: implications for future treatment strategies. Futur Sci OA 2(1):FSO84. https://doi.org/10.4155/fso.15.84

    Article  CAS  Google Scholar 

  52. Zhang Y, Gong XG, Wang ZZ, Sun HM, Guo ZY, Hu JH, Ma L, Li P et al (2016) Overexpression of DJ-1/PARK7, the Parkinson’s disease-related protein, improves mitochondrial function via Akt phosphorylation on threonine 308 in dopaminergic neuron-like cells. Eur J Neurosci 43(10):1379–1388. https://doi.org/10.1111/ejn.13216

    Article  CAS  PubMed  Google Scholar 

  53. Xu Y, Liu C, Chen S, Ye Y, Guo M, Ren Q, Liu L, Zhang H et al (2014) Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson’s disease. Cell Signal 26(8):1680–1689. https://doi.org/10.1016/j.cellsig.2014.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Greene LA, Levy O, Malagelada C (2011) Akt as a victim, villain and potential hero in Parkinson’s disease pathophysiology and treatment. Cell Mol Neurobiol 31(7):969–978. https://doi.org/10.1007/s10571-011-9671-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Murata H, Sakaguchi M, Jin Y, Sakaguchi Y, Futami J, Yamada H, Kataoka K, Huh NH (2011) A new cytosolic pathway from a Parkinson disease-associated kinase, BRPK/PINK1: activation of AKT via mTORC2. J Biol Chem 286(9):7182–7189. https://doi.org/10.1074/jbc.M110.179390

    Article  CAS  PubMed  Google Scholar 

  56. Thornton C, Leaw B, Mallard C, Nair S, Jinnai M, Hagberg H (2017) Cell death in the developing brain after hypoxia-ischemia. Front Cell Neurosci 11:248. https://doi.org/10.3389/fncel.2017.00248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. McIlwain DR, Berger T, Mak TW (2013) Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 5(4):a008656. https://doi.org/10.1101/cshperspect.a008656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu XR, Li YQ, Hua C, Li SJ, Zhao G, Song HM, Yu MX, Huang Q (2015) Oxidative stress inhibits growth and induces apoptotic cell death in human U251 glioma cells via the caspase-3-dependent pathway. Eur Rev Med Pharmacol Sci 19(21):4068–4075

    PubMed  Google Scholar 

  59. Meng XW, Fraser MJ, Feller JM, Ziegler JB (2000) Caspase-3-dependent and caspase-3-independent pathways leading to chromatin DNA fragmentation in HL-60 cells. Apoptosis 5(1):61–67

    Article  CAS  PubMed  Google Scholar 

  60. Liu X, Kim CN, Yang J, Jemmerson R, Wang X (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86(1):147–157

    Article  CAS  PubMed  Google Scholar 

  61. Zhang J, Qian H, Zhao P, Hong SS, Xia Y (2006) Rapid hypoxia preconditioning protects cortical neurons from glutamate toxicity through delta-opioid receptor. Stroke 37(4):1094–1099. https://doi.org/10.1161/01.STR.0000206444.29930.18

    Article  CAS  PubMed  Google Scholar 

  62. Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802(4):396–405. https://doi.org/10.1016/j.bbadis.2009.12.009

    Article  CAS  PubMed  Google Scholar 

  63. Correa SA, Eales KL (2012) The role of p38 MAPK and its substrates in neuronal plasticity and neurodegenerative disease. J Signal Transduction 2012:649079. https://doi.org/10.1155/2012/649079

    Article  CAS  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (81590953, 81574053, 81303027), Jiangsu Provincial Special Program of Medical Science (BL2014035), Changzhou Science and Technology Support Program (CE20155060, CE20165048), Changzhou High-Level Medical Talents Training Project (2016CZBJ006), Changzhou Municipal Commissions of Health and Family Planning Major Scientific and Technological Project (ZD201620), Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function (14DZ2260500), and Science and Technology Commission of Shanghai Municipality (15441903800).

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  1. Yuan Xu and Feng Zhi contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, The First People’s Hospital of Changzhou, Changzhou, Jiangsu, China

    Yuan Xu, Feng Zhi, Ya Peng, Naiyuan Shao & Yilin Yang

  2. Modern Medical Research Center, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China

    Yuan Xu, Feng Zhi & Yilin Yang

  3. Royal College of Surgeons of Ireland – Medical University of Bahrain, Busaiteen, Bahrain

    Dhiaedin Khiati

  4. Department of Life and Environment Sciences, University of Cagliari, Cagliari, Italy

    Gianfranco Balboni

  5. Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China

    Ying Xia

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Dr. Ying Xia is the first corresponding author and Dr. Yilin Yang is the co-corresponding author.

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Xu, Y., Zhi, F., Peng, Y. et al. δ-Opioid Receptor Activation Attenuates Hypoxia/MPP+-Induced Downregulation of PINK1: a Novel Mechanism of Neuroprotection Against Parkinsonian Injury. Mol Neurobiol 56, 252–266 (2019). https://doi.org/10.1007/s12035-018-1043-7

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