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MicroRNA-93 Blocks Signal Transducers and Activator of Transcription 3 to Reduce Neuronal Damage in Parkinson’s Disease

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Abstract

MicroRNA-93 (miR-93) is an oncogene that promotes tumor growth and angiogenesis. However, its role in Parkinson’s disease (PD) remains unknown. This study aimed at investigating the role of miR-93 in PD and the molecular mechanisms involved. 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mouse model and lipopolysaccharide (LPS)-exposed BV2 cells were constructed. Real-time quantitative PCR was used to detect the mRNA expression of miR-93, iNOS, IL-6, IL-10, TNF-α and TGF-β1. Bioinformatics analysis and luciferase reporter assay were used to predict and confirm the interaction between miR-93 and STAT3. Flow cytometry was used to detect cell apoptosis. Western blotting was used to detect the protein expression of STAT3. Immunohistochemistry was used to analyze the Iba1-positive and TH positive cells. It was found that the expression of miR-93 was down-regulated in LPS-exposed BV2 cells. Overexpression of miR-93 inhibited the expression of iNOS, IL-6 and TNF-α, while enhanced the expression of TGF-β1 and IL-10. The expression of transcriptional activator 3 (STAT3) was found to be up-regulated in LPS-exposed BV2 cells. Knockdown of STAT3 inhibited the expression of iNOS, IL-6 and TNF-α, while enhanced the expression of TGF-β1 and IL-10. Moreover, STAT3 was found to be a direct target of miR-93, and miR-93 overexpression inhibited the expression of STAT3. Furthermore, both miR-93 overexpression and STAT3 knockdown reduced LPS-induced BV2 cell apoptosis, whereas STAT3 overexpression eliminated the inhibitory effect of miR-93 on LPS-induced BV2 cell apoptosis. In addition, miR-93 overexpression inhibited MPTP-induced STAT3 expression, microglial activation and inflammatory reaction and reduced the loss of tyrosine hydroxylase in the substantia nigra of mice. In conclusion, we demonstrate that miR-93 may be involved in PD by regulating the expression of STAT3.

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Data Availability

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Abbreviations

PD:

Parkinson’s disease

MiRs:

MicroRNAs

LPS:

Lipopolysaccharide

STAT3:

Signal transductors and transcriptional activator 3

References

  1. Hill-Burns EM et al (2017) Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome. Mov Disord 32(5):739–749

    Article  CAS  Google Scholar 

  2. Picca A et al (2020) Mitochondrial signatures in circulating extracellular vesicles of older adults with Parkinson’s disease: results from the EXosomes in PArkiNson’s Disease (EXPAND) study. J Clin Med 9(2):504

    Article  CAS  Google Scholar 

  3. Burbulla LF et al (2017) Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 357(6357):1255–1261

    Article  CAS  Google Scholar 

  4. Lill CM (2016) Genetics of Parkinson’s disease. Mol Cell Probes 30(6):386–396

    Article  CAS  Google Scholar 

  5. Hoss AG et al (2016) microRNA profiles in Parkinson’s disease prefrontal cortex. Front Aging Neurosci 8:36

    Article  Google Scholar 

  6. Cao X-Y et al (2017) MicroRNA biomarkers of Parkinson’s disease in serum exosome-like microvesicles. Neurosci Lett 644:94–99

    Article  CAS  Google Scholar 

  7. Ding H et al (2016) Identification of a panel of five serum miRNAs as a biomarker for Parkinson’s disease. Parkinsonism Relat Disord 22:68–73

    Article  Google Scholar 

  8. Thome AD et al (2016) microRNA-155 regulates alpha-synuclein-induced inflammatory responses in models of Parkinson disease. J Neurosci 36(8):2383–2390

    Article  CAS  Google Scholar 

  9. Taguchi Y, Wang H (2018) Exploring MicroRNA biomarkers for Parkinson’s disease from mRNA expression profiles. Cells 7(12):245

    Article  CAS  Google Scholar 

  10. Li S et al (2016) MicroRNA-7 inhibits neuronal apoptosis in a cellular Parkinson’s disease model by targeting Bax and Sirt2. Am J Transl Res 8(2):993

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Yao L et al (2019) MicroRNA-124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson’s disease. FASEB J 33(7):8648–8665

    Article  CAS  Google Scholar 

  12. Fang L et al (2011) MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-β8. Oncogene 30(7):806

    Article  CAS  Google Scholar 

  13. Yang T et al (2016) Elevated serum miR-93, miR-191, and miR-499 are noninvasive biomarkers for the presence and progression of traumatic brain injury. J Neurochem 137(1):122–129

    Article  CAS  Google Scholar 

  14. Choi D-J, Kwon J-K, Joe E-H (2018) A Parkinson’s disease gene, DJ-1, regulates astrogliosis through STAT3. Neurosci Lett 685:144–149

    Article  CAS  Google Scholar 

  15. Zhang J et al (2019) miR-let-7a suppresses α-Synuclein-induced microglia inflammation through targeting STAT3 in Parkinson’s disease. Biochem Biophys Res Commun 519(4):740–746

    Article  CAS  Google Scholar 

  16. Wang B et al (2016) Neuroprotective effects of nitidine in Parkinson’s disease models through inhibiting microglia activation: role of the Jak2–Stat3 pathway. RSC Adv 6(75):71328–71337

    Article  CAS  Google Scholar 

  17. Yan A et al (2019) Idebenone alleviates neuroinflammation and modulates microglial polarization in LPS-stimulated BV2 cells and MPTP-induced Parkinson’s disease mice. Front Cell Neurosci 12:529

    Article  Google Scholar 

  18. Hantraye P et al (1996) Inhibition of neuronal nitric oxide synthase prevents MPTP–induced Parkinsonism in baboons. Nat Med 2(9):1017–1021

    Article  CAS  Google Scholar 

  19. Friedman BA et al (2018) Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer’s disease not evident in mouse models. Cell Rep 22(3):832–847

    Article  CAS  Google Scholar 

  20. Burguillos M et al (2011) Apoptosis-inducing factor mediates dopaminergic cell death in response to LPS-induced inflammatory stimulus: evidence in Parkinson’s disease patients. Neurobiol Dis 41(1):177–188

    Article  CAS  Google Scholar 

  21. Dutta G, Zhang P, Liu B (2008) The lipopolysaccharide Parkinson’s disease animal model: mechanistic studies and drug discovery. Fundam Clin Pharmacol 22(5):453–464

    Article  CAS  Google Scholar 

  22. Qin L et al (2005) Interactive role of the toll-like receptor 4 and reactive oxygen species in LPS-induced microglia activation. Glia 52(1):78–84

    Article  Google Scholar 

  23. Zhou Y et al (2016) MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson’s disease. Mol Neurodegener 11(1):28

    Article  Google Scholar 

  24. Yao L et al (2018) MicroRNA-124 regulates the expression of MEKK3 in the inflammatory pathogenesis of Parkinson’s disease. J Neuroinflammation 15(1):13

    Article  Google Scholar 

  25. Yan X-T et al (2017) MicroRNA-93 alleviates neuropathic pain through targeting signal transducer and activator of transcription 3. Int Immunopharmacol 46:156–162

    Article  CAS  Google Scholar 

  26. Foshay KM, Gallicano GI (2009) miR-17 family miRNAs are expressed during early mammalian development and regulate stem cell differentiation. Dev Biol 326(2):431–443

    Article  CAS  Google Scholar 

  27. Xiong L, Yu K, Zhen S (2018) MiR-93 blocks STAT3 to alleviate hepatic injury after ischemia–reperfusion. Eur Rev Med Pharmacol Sci 22(16):5295–5304

    CAS  PubMed  Google Scholar 

  28. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809

    Article  CAS  Google Scholar 

  29. Bromberg J, Wang TC (2009) Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell 15(2):79–80

    Article  CAS  Google Scholar 

  30. Liu M, Bing G (2011) Lipopolysaccharide animal models for Parkinson’s disease. Parkinson’s Dis. https://doi.org/10.4061/2011/327089

    Article  Google Scholar 

  31. Forno L et al (1993) Similarities and differences between MPTP-induced parkinsonsim and Parkinson’s disease. Neuropathologic considerations. Adv Neurol 60:600–608

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Xiufeng Wang, Zhijun Liu & Fang Wang

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  1. Xiufeng Wang
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  2. Zhijun Liu
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  3. Fang Wang
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Contributions

ZL analyzed and interpreted the data, XW drafted the manuscript. FW trained the interviewers for data collection. All authors read and approved the final manuscript.

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Correspondence to Fang Wang.

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The authors declare that they have no competing interests.

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Ethical clearance was obtained through the Ethics Review Committee, Faculty of Medicine, Union Hospital and the informed consent was obtained from all participants. Data collected from participants were kept confidential and were accessible only to the researchers.

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Wang, X., Liu, Z. & Wang, F. MicroRNA-93 Blocks Signal Transducers and Activator of Transcription 3 to Reduce Neuronal Damage in Parkinson’s Disease. Neurochem Res 46, 1859–1868 (2021). https://doi.org/10.1007/s11064-021-03333-x

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  • DOI: https://doi.org/10.1007/s11064-021-03333-x

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