Skip to main content

Advertisement

SpringerLink
Log in

Circular RNA circ_0070441 regulates MPP+-triggered neurotoxic effect in SH-SY5Y cells via miR-626/IRS2 axis

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Circular RNAs (circRNAs) was suggested to play crucial regulatory roles in various human diseases, including Parkinson’s disease (PD). This research aimed to investigate the function and potential mechanism of circ_0070441 in PD. MPP+ (1-methyl-4-phenylpyridinium)-treated SH-SY5Y cells was used as an in vitro cellular PD model. The expressions of circ_0070441, microRNA (miR)-626 and insulin receptor substrate 2 (IRS2) were measured by quantitative real-time polymerase chain reaction (RT-qPCR) or western blot. Cell Counting Kit-8 (CCK-8) assay, Cytotoxicity Detection Kit (Lactate Dehydrogenase), flow cytometry and Caspase-3 Assay Kit were used to detect cell viability, LDH release, cell apoptosis and caspase-3 activity, respectively. The levels of inflammation-related factors were detected by enzyme-linked immunosorbent assay (ELISA). The correlation among circ_0070441, miR-626 and IRS2 were confirmed by dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull-down assay. The levels of circ_0070441 and IRS2 were increased while miR-626 expression was decreased in MPP+-treated SH-SY5Y cells in dose- and time-dependent manners. Depletion of circ_0070441 alleviated MPP+-triggered neuronal damage by regulating cell apoptosis and inflammation. Circ_0070441 acted as a sponge for miR-626, and IRS2 was a target of miR-626. Besides, the neuroprotective effects of circ_0070441 knockdown or miR-626 overexpression were partly overturned by the suppression of miR-626 or IRS2 overexpression. Moreover, circ_0070441 upregulated IRS2 expression by interacting with miR-626. In summary, circ_0070441 aggravated MPP+-triggered neurotoxic effect in SH-SY5Y cells by regulating miR-626/IRS2 axis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

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

References

  • Armstrong MJ, Okun MS (2020) Diagnosis and treatment of Parkinson disease: a review. JAMA 323(6):548–560

    Article  Google Scholar 

  • Ascherio A, Schwarzschild MA (2016) The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol 15(12):1257–1272

    Article  Google Scholar 

  • Coelho M, Ferreira JJ (2012) Late-stage Parkinson disease. Nat Rev Neurol 8(8):435–442

    Article  CAS  Google Scholar 

  • D’Ambra E, Capauto D, Morlando M (2019) Exploring the regulatory role of circular RNAs in neurodegenerative disorders. Int J Mol Sci 20(21):5477

    Article  Google Scholar 

  • Ding XM, Zhao LJ, Qiao HY, Wu SL, Wang XH (2019) Long non-coding RNA-p21 regulates MPP(+)-induced neuronal injury by targeting miR-625 and derepressing TRPM2 in SH-SY5Y cells. Chem Biol Interact 307:73–81

    Article  CAS  Google Scholar 

  • Dong W, Bi J, Liu H, Yan D, He Q, Zhou Q et al (2019) Circular RNA ACVR2A suppresses bladder cancer cells proliferation and metastasis through miR-626/EYA4 axis. Mol Cancer 18(1):95

    Article  Google Scholar 

  • Gámez-Valero A, Guisado-Corcoll A, Herrero-Lorenzo M, Solaguren-Beascoa M, Martí E (2020) Non-coding RNAs as sensors of oxidative stress in neurodegenerative diseases. Antioxidants (Basel) 9(11):1095

    Article  Google Scholar 

  • Hallett PJ, Engelender S, Isacson O (2019) Lipid and immune abnormalities causing age-dependent neurodegeneration and Parkinson’s disease. J Neuroinflammation 16(1):153

    Article  Google Scholar 

  • Hanan M, Simchovitz A, Yayon N, Vaknine S, Cohen-Fultheim R, Karmon M et al (2020) A Parkinson’s disease CircRNAs Resource reveals a link between circSLC8A1 and oxidative stress. EMBO Mol Med 12(9):e11942

    Article  CAS  Google Scholar 

  • Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK et al (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495(7441):384–388

    Article  CAS  Google Scholar 

  • Jia E, Zhou Y, Liu Z, Wang L, Ouyang T, Pan M et al (2020) Transcriptomic profiling of circular RNA in different brain regions of Parkinson’s disease in a mouse model. Int J Mol Sci 21(8):3006

    Article  CAS  Google Scholar 

  • Juzwik CA, S SD, Zhang Y, Paradis-Isler N, Sylvester A, Amar-Zifkin A et al (2019) microRNA dysregulation in neurodegenerative diseases: A systematic review. Prog Neurobiol 182:101664

    Article  CAS  Google Scholar 

  • Kalia LV, Lang AE (2015) Parkinson’s disease. Lancet 386(9996):896–912

    Article  CAS  Google Scholar 

  • Khoo SK, Petillo D, Kang UJ, Resau JH, Berryhill B, Linder J et al (2012) Plasma-based circulating MicroRNA biomarkers for Parkinson’s disease. J Parkinsons Dis 2(4):321–331

    Article  CAS  Google Scholar 

  • Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J (2019) The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet 20(11):675–691

    Article  CAS  Google Scholar 

  • Liu Q, Cao G, Wan Y, Xu C, He Y, Li G (2021) Hsa_circ_0001073 targets miR-626/LIFR axis to inhibit lung cancer progression. Environ Toxicol 36(6):1052–1060

    Article  CAS  Google Scholar 

  • Peng T, Liu X, Wang J, Liu Y, Fu Z, Ma X et al (2019) Long noncoding RNA HAGLROS regulates apoptosis and autophagy in Parkinson’s disease via regulating miR-100/ATG10 axis and PI3K/Akt/mTOR pathway activation. Artif Cells Nanomed Biotechnol 47(1):2764–2774

    Article  CAS  Google Scholar 

  • Qin LX, Tan JQ, Zhang HN, Tang JG, Jiang B, Shen XM et al (2019) Preliminary study of hsa-miR-626 change in the cerebrospinal fluid of Parkinson’s disease patients. J Clin Neurosci 70:198–201

    Article  CAS  Google Scholar 

  • Qin LX, Tan JQ, Zhang HN, Tang JG, Jiang B, Shen XM et al (2021) Preliminary study of hsa-mir-626 change in the cerebrospinal fluid in Parkinson’s disease. Neurol India 69(1):115–118

    Article  Google Scholar 

  • Ravanidis S, Bougea A, Karampatsi D, Papagiannakis N, Maniati M, Stefanis L et al (2021) Differentially expressed circular RNAs in peripheral blood mononuclear cells of patients with Parkinson’s disease. Mov Disord 36(5):1170–1179

    Article  CAS  Google Scholar 

  • Rostamian Delavar M, Baghi M, Safaeinejad Z, Kiani-Esfahani A, Ghaedi K, Nasr-Esfahani MH (2018) Differential expression of miR-34a, miR-141, and miR-9 in MPP+-treated differentiated PC12 cells as a model of Parkinson’s disease. Gene 662:54–65

    Article  CAS  Google Scholar 

  • Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP (2011) A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146(3):353–358

    Article  CAS  Google Scholar 

  • Sang Q, Liu X, Wang L, Qi L, Sun W, Wang W et al (2018) CircSNCA downregulation by pramipexole treatment mediates cell apoptosis and autophagy in Parkinson’s disease by targeting miR-7. Aging 10(6):1281–1293

    Article  CAS  Google Scholar 

  • Schildknecht S, Di Monte DA, Pape R, Tieu K, Leist M (2017) Tipping points and endogenous determinants of nigrostriatal degeneration by MPTP. Trends Pharmacol Sci 38(6):541–555

    Article  CAS  Google Scholar 

  • Shi J, Bao X, Liu Z, Zhang Z, Chen W, Xu Q (2019) Serum miR-626 and miR-5100 are promising prognosis predictors for oral squamous cell carcinoma. Theranostics 9(4):920–931

    Article  CAS  Google Scholar 

  • Soreq L, Ben-Shaul Y, Israel Z, Bergman H, Soreq H (2012) Meta-analysis of genetic and environmental Parkinson’s disease models reveals a common role of mitochondrial protection pathways. Neurobiol Dis 45(3):1018–1030

    Article  CAS  Google Scholar 

  • Sun Q, Wang S, Chen J, Cai H, Huang W, Zhang Y et al (2019) MicroRNA-190 alleviates neuronal damage and inhibits neuroinflammation via Nlrp3 in MPTP-induced Parkinson’s disease mouse model. J Cell Physiol 234(12):23379–23387

    Article  CAS  Google Scholar 

  • Wakabayashi T, Yamaguchi K, Matsui K, Sano T, Kubota T, Hashimoto T et al (2019) Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer’s disease. Mol Neurodegener 14(1):15

    Article  Google Scholar 

  • Wang M, Sun H, Yao Y, Tang X, Wu B (2019) MicroRNA-217/138-5p downregulation inhibits inflammatory response, oxidative stress and the induction of neuronal apoptosis in MPP(+)-induced SH-SY5Y cells. Am J Transl Res 11(10):6619–6631

    CAS  PubMed  PubMed Central  Google Scholar 

  • White MF (2002) IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab 283(3):E413–E422

    Article  CAS  Google Scholar 

  • White MF (2014) IRS2 integrates insulin/IGF1 signalling with metabolism, neurodegeneration and longevity. Diabetes Obes Metab 16(Suppl 1):4–15

    Article  CAS  Google Scholar 

  • Xie Y, Zhang S, Lv Z, Long T, Luo Y, Li Z (2021) SOX21-AS1 modulates neuronal injury of MMP(+)-treated SH-SY5Y cells via targeting miR-7-5p and inhibiting IRS2. Neurosci Lett 746:135602

    Article  CAS  Google Scholar 

  • Yang L, Mao K, Yu H, Chen J (2020) Neuroinflammatory responses and Parkinson’ disease: pathogenic mechanisms and therapeutic targets. J Neuroimmune Pharmacol 15(4):830–837

    Article  Google Scholar 

  • Zhou DN, Ye CS, Deng YF (2020) CircRNAs: potency of protein translation and feasibility of novel biomarkers and therapeutic targets for head and neck cancers. Am J Transl Res 12(5):1535–1552

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu P, Liang H, Huang X, Zeng Q, Liu Y, Lv J et al (2020) Circular RNA Hsa_circ_0004018 inhibits Wnt/β-catenin signaling pathway by targeting microRNA-626/DKK3 in hepatocellular carcinoma. Onco Targets Ther 13:9351–9364

    Article  CAS  Google Scholar 

Download references

Funding

The project was funded by Ningxia Hui Autonomous Region Key Research and Development Project (No. 2017BY037) and Ningxia Natural Science Foundation Project (No. NZ17189).

Author information

Authors and Affiliations

  1. Department of Neurology, People’s Hospital of Ningxia Hui Autonomous Region, Zhengyuan North Street, Jinfeng District, Yinchuan, 750002, China

    Xuqing Cao, Dong Xu, Tao Zhang, Haiping Han, Tingjie Ma, Mingshan Qi & Jing He

  2. Department of Rheumatogy and Immunology, People’s Hospital of Ningxia Hui Autonomous Region, 750002, Yinchuan, China

    Jiangtao Guo

  3. Department of Neurology, Osaka University Graduate School of Medicine, 550-0004, Osaka, Japan

    Hideki Mochizuki

Authors
  1. Xuqing Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiangtao Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hideki Mochizuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haiping Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tingjie Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mingshan Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jing He
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XC and JG designed, supervised the study, conducted the experiments and drafted the manuscript. DX, TZ and HH collected and analyzed the data. HM and TM contributed the methodology and analyzed the data. MQ and JH operated the software and edited the manuscript. XC was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xuqing Cao.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xuqing Cao and Jiangtao Guo are co-authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cao, X., Guo, J., Mochizuki, H. et al. Circular RNA circ_0070441 regulates MPP+-triggered neurotoxic effect in SH-SY5Y cells via miR-626/IRS2 axis. Metab Brain Dis 37, 513–524 (2022). https://doi.org/10.1007/s11011-021-00869-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-021-00869-3

Keywords

Search

Navigation