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Long non-coding RNA UCA1 regulates MPP+-induced neuronal damage through the miR-671-5p/KPNA4 pathway in SK-N-SH cells

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Abstract

Parkinson’s disease (PD) is an age-related neurodegenerative disease. Long non-coding RNA urothelial carcinoma-associated 1 (UCA1) is involved in the pathogenesis of PD. However, the pathogenesis of PD regulated by UCA1 has not been fully explained. We used 1-Methyl-4-phenylpyridinium (MPP+)-induced SK-N-SH cells for functional analysis. Expression levels of UCA1, microRNA (miR)-671-5p, and KPNA4 (karyopherin subunit alpha 4) mRNA were detected using quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability and apoptosis were analyzed using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) or flow cytometry assays. Some protein levels were measured by western blotting. The levels of pro-inflammatory cytokines were tested by ELISA (enzyme-linked immunosorbent assay). The levels of LDH (lactate dehydrogenase), MDA (malondialdehyde), and SOD (superoxide dismutase) were measured using corresponding kits. The relationship between UCA1 or KPNA4 and miR-671-5p was verified by dual-luciferase reporter assay and/or RNA immunoprecipitation (RIP) assay. MPP+ induced UCA1 expression in SK-N-SH cells in a concentration-dependent manner or time-dependent manner. UCA1 knockdown reduced MPP+-induced apoptosis, inflammation, and oxidative stress in SK-N-SH cells. MiR-671-5p was downregulated while KPNA4 was upregulated in MPP+-treated SK-N-SH cells. UCA1 sponged miR-671-5p to regulate KPNA4 expression. MiR-671-5p inhibition counteracted UCA1 knockdown-mediated influence on apoptosis, inflammation, and oxidative stress of MPP+-induced SK-N-SH cells. KPNA4 overexpression offset the inhibitory influence of miR-671-5p mimic on apoptosis, inflammation, and oxidative stress of MPP+-treated SK-N-SH cells. UCA1 inhibition reduced MPP+-induced neuronal damage through the miR-671-5p/KPNA4 pathway in SK-N-SH cells, providing a novel mechanism to understand the pathogenesis of PD.

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References

  • Cacabelos R (2017) Parkinson’s, Disease: From pathogenesis to pharmacogenomics. Int J Mol Sci 18(3):551

  • Cai L, Tu L, Li T, Yang X, Ren Y, Gu R, Zhang Q, Yao H, Qu X, Wang Q, Tian J (2019) Downregulation of lncRNA UCA1 ameliorates the damage of dopaminergic neurons, reduces oxidative stress and inflammation in Parkinson’s disease through the inhibition of the PI3K/Akt signaling pathway. Int Immunopharmacol 75:105734

    Article  CAS  PubMed  Google Scholar 

  • Cao Z, Pan X, Yang Y, Huang Y, Shen H-B (2018) The lncLocator: a subcellular localization predictor for long non-coding RNAs based on a stacked ensemble classifier. Bioinf (Oxford England) 34:2185–2194

    Article  CAS  Google Scholar 

  • Chen J, Zeng L, Xia T, Li S, Yan T, Wu S, Qiu G, Liu Z (2015) Toward a biomarker of oxidative stress: a fluorescent probe for exogenous and endogenous malondialdehyde in living cells. Anal Chem 87:8052–8056

    Article  CAS  PubMed  Google Scholar 

  • Corti O, Lesage S, Brice A (2011) What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol Rev 91:1161–1218

  • Dias V, Junn E, Mouradian MM (2013) The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis 3:461–491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fagerlund R, Kinnunen L, Köhler M, Julkunen I, Melén (2005) K NF-{kappa}B is transported into the nucleus by importin {alpha}3 and importin {alpha}4. J Biol Chem 280:15942–15951

    Article  CAS  PubMed  Google Scholar 

  • Francelle L, Galvan L, Gaillard M-C, Petit F, Bernay B, Guillermier M, Bonvento G, Dufour N, Elalouf J-M, Hantraye P, Déglon N, de Chaldée M (2015) Brouillet E Striatal long noncoding RNA Abhd11os is neuroprotective against an N-terminal fragment of mutant huntingtin in vivo. Neurobiol Aging 36:1601.e1607-1601.1616

    Article  Google Scholar 

  • Gao H-M, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VMY (2008) Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci: Off J Soc Neurosci 28:7687–7698

    Article  CAS  Google Scholar 

  • Ghosh A, Tyson T, George S, Hildebrandt EN, Steiner JA, Madaj Z, Schulz E, Machiela E, McDonald WG, Escobar Galvis ML, Kordower JH, Van Raamsdonk JM, Colca JR (2016) Brundin P Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson’s disease. Sci Transl Med 8:368ra174

    Article  PubMed  Google Scholar 

  • Gonçalves AP, Máximo V, Lima J, Singh KK, Soares P, Videira A (2011) Involvement of p53 in cell death following cell cycle arrest and mitotic catastrophe induced by rotenone. Biochim Biophys Acta 1813:492–499

    Article  PubMed  PubMed Central  Google Scholar 

  • Hauser DN, Hastings TG (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiol Dis 51:35–42

    Article  CAS  PubMed  Google Scholar 

  • Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol 8:382–397

    Article  CAS  PubMed  Google Scholar 

  • Hu X, Ma R, Fu W, Zhang C, Du X (2019) LncRNA UCA1 sponges miR-206 to exacerbate oxidative stress and apoptosis induced by ox-LDL in human macrophages. J Cell Physiol 234:14154–14160

    Article  CAS  PubMed  Google Scholar 

  • Li X, Diao H, Circular (2019) RNA circ_0001946 acts as a competing endogenous RNA to inhibit glioblastoma progression by modulating miR-671-5p and CDR1. J Cell Physiol 234:13807–13819

  • Lin Q, Hou S, Dai Y, Jiang N, Lin Y (2019) LncRNA HOTAIR targets miR-126-5p to promote the progression of Parkinson’s disease through RAB3IP. Biol Chem 400:1217–1228

    Article  CAS  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods (San Diego, Calif) 25:402–408

  • Lu M, Sun WL, Shen J, Wei M, Chen B, Qi YJ, Xu CS (2018) LncRNA-UCA1 promotes PD development by upregulating SNCA. Eur Rev Med Pharmacol Sci 22:7908–7915

    CAS  PubMed  Google Scholar 

  • Marchenko ND, Hanel W, Li D, Becker K, Reich N, Moll UM (2010) Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-alpha3 binding. Cell Death Differ 17:255–267

    Article  CAS  PubMed  Google Scholar 

  • Nakamori M, Junn E, Mochizuki H, Mouradian MM (2019) Nucleic acid-based therapeutics for Parkinson’s disease. Neurotherapeutics 16:287–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nan A, Chen L, Zhang N, Liu Z, Yang T, Wang Z, Yang C (2017) Jiang Y A novel regulatory network among LncRpa, CircRar1, MiR-671 and apoptotic genes promotes lead-induced neuronal cell apoptosis. Arch Toxicol 91:1671–1684

    Article  CAS  PubMed  Google Scholar 

  • Ping X, Cheng Y, Bao J, Shi K, Zou J, Shentu X (2021) KPNA4 is involved in cataract formation via the nuclear import of p53. Gene 786:145621

    Article  CAS  PubMed  Google Scholar 

  • Rashid F, Shah A, Shan G (2016) Long non-coding RNAs in the cytoplasm. Genom Proteom Bioinform 14:73–80

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Savitt JM, Dawson VL, Dawson TM (2006) Diagnosis and treatment of Parkinson disease: molecules to medicine. J Clin Investig 116:1744–1754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi CH, Huang Y, Li WQ, Chen RG (2019) Influence of LncRNA UCA1 on glucose metabolism in rats with diabetic nephropathy through PI3K-Akt signaling pathway. Eur Rev Med Pharmacol Sci 23:10058–10064

    PubMed  Google Scholar 

  • Song H, Xu Y, Xu T, Fan R, Jiang T, Cao M, Shi L, Song J (2020) CircPIP5K1A activates KRT80 and PI3K/AKT pathway to promote gastric cancer development through sponging miR-671-5p. J Cell Physiol 126:109941

    CAS  Google Scholar 

  • Subramaniam SR, Chesselet M-F (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol 106–107:17–32

    Article  PubMed  Google Scholar 

  • Sun S-C (2017) The non-canonical NF-κB pathway in immunity and inflammation. Nat Rev Immunol 17:545–558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37:510–518

    Article  CAS  PubMed  Google Scholar 

  • Thomson DW, Dinger ME (2016) Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet 17:272–283

    Article  CAS  PubMed  Google Scholar 

  • Uwatoko H, Hama Y, Iwata IT, Shirai S, Matsushima M, Yabe I, Utsumi J, Sasaki H (2019) Identification of plasma microRNA expression changes in multiple system atrophy and Parkinson’s disease. Mol Brain 12:49

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang D-Q, Fu P, Yao C, Zhu L-S, Hou T-Y, Chen J-G, Lu Y, Liu D, Zhu L-Q (2018) Long non-coding RNAs, novel culprits, or bodyguards in neurodegenerative diseases. Mol Ther Nucleic Acids 10:269–276

    Article  CAS  PubMed  Google Scholar 

  • Wang X-S, Zhang Z, Wang H-C, Cai J-L, Xu Q-W, Li M-Q, Chen Y-C, Qian X-P, Lu T-J, Yu L-Z, Zhang Y, Xin D-Q, Na Y-Q, Chen W-F (2006) Rapid identification of UCA1 as a very sensitive and specific unique marker for human bladder carcinoma. Clin Cancer Res 12:4851–4858

    Article  CAS  PubMed  Google Scholar 

  • Xie X-X, Kou S-T, Pu Z-H, Hou C-Y, Tian Y-P (2007) Effects of scalp catgut embedding on SOD, NO, MDA in the rat with Parkinson’s disease. Zhongguo Zhen Jiu = Chin Acupuncture & Moxibustion 27:753–756

    CAS  Google Scholar 

  • Xing R-X, Li L-G, Liu X-W, Tian B-X, Cheng Y (2020) Down regulation of miR-218, miR-124, and miR-144 relates to Parkinson’s disease via activating NF-κB signaling. Kaohsiung J Med Sci 36:786–792

    Article  CAS  PubMed  Google Scholar 

  • Xu Z, Cawthon D, McCastlain KA, Duhart HM, Newport GD, Fang H, Patterson TA, Slikker W Jr (2005) Ali SF Selective alterations of transcription factors in MPP+-induced neurotoxicity in PC12 cells. Neurotoxicology 26:729–737

    Article  CAS  PubMed  Google Scholar 

  • Xue M, Chen W, Li X (2016) Urothelial cancer associated 1: a long noncoding RNA with a crucial role in cancer. J Cancer Res Clin Oncol 142:1407–1419

    Article  PubMed  Google Scholar 

  • Yi J, Chen B, Yao X, Lei Y, Ou F, Huang F (2019) Upregulation of the lncRNA MEG3 improves cognitive impairment, alleviates neuronal damage, and inhibits activation of astrocytes in hippocampus tissues in Alzheimer’s disease through inactivating the PI3K/Akt signaling pathway. J Cell Biochem 120:18053–18065

    Article  CAS  PubMed  Google Scholar 

  • Zella MAS, Metzdorf J, Ostendorf F, Maass F, Muhlack S, Gold R, Haghikia A, Tönges L (2019) Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson’s disease. Cells 8(2):105

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Authors and Affiliations

  1. Department of Neurosurgery, Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Xinghualing District, Taiyuan City, Shanxi Province, 030001, China

    Zhengheng Hao, Qingfeng Zhu & Jianxing Xu

  2. Department of Pharmacy, Second Hospital of Shanxi Medical University, 030001, Taiyuan, Shanxi, China

    Wen Dang

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  1. Zhengheng Hao
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  2. Wen Dang
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  3. Qingfeng Zhu
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  4. Jianxing Xu
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Zhengheng Hao designed and performed the research; Wen Dang, Qingfeng Zhu, Jianxing Xu analyzed the data; Zhengheng Hao wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Qingfeng Zhu.

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Supplementary Fig. 1

(A) Protein levels of p-p65 and p65 in SK-N-SH cells at different groups (Control, MMP+, MMP++miR-NC, MMP++miR-671-5p, MMP++miR-671-5p + vector, or MMP++miR-671-5p + KPNA4) were detected. (C) The viability of SK-N-SH cells treated with different concentrations of MPP+ (0, 0.5, 1, 2, 4 mM) was determined. (C) Transfection efficiencies of three siRNAs were evaluated. *P < 0.05. (PNG 320 KB)

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Hao, Z., Dang, W., Zhu, Q. et al. Long non-coding RNA UCA1 regulates MPP+-induced neuronal damage through the miR-671-5p/KPNA4 pathway in SK-N-SH cells. Metab Brain Dis 38, 961–972 (2023). https://doi.org/10.1007/s11011-022-01118-x

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