Skip to main content

Advertisement

SpringerLink
Log in

MicroRNA-326 Inhibits Apoptosis and Promotes Proliferation of Dopaminergic Neurons in Parkinson’s Disease Through Suppression of KLK7-Mediated MAPK Signaling Pathway

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Parkinson’s disease (PD), one of the motor system disorders, is characterized by the loss of dopamine-producing brain cells. Accumulating evidence has highlighted the involvement of microRNAs (miRs) in the development and progression of PD. Hence, we aimed at exploring possible effects of miR-326 on the progression of PD in mice in an attempt to elucidate the underlying mechanism associated with the kallikrein-related peptidase 7 (KLK7)–mediated mitogen-activated protein kinase (MAPK) signaling pathway. In order to identify the regulatory relationship between miR-326 and KLK7 and its biological significance in PD, PD mouse models were established and subsequently treated with mimics or inhibitors of miR-326 or siRNA-KLK7. The content of striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyrosine (3-MT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA); positive expression of tyrosine hydroxylase (TH) and inducible nitric oxide synthase (iNOS); and the levels of IL-1, IL-6, TNF-α, INF-γ, and MAPK signaling pathway–related genes were determined accordingly. The results obtained indicated that KLK7 was negatively targeted by miR-326, with lower miR-326 and higher KLK7 detected among PD mice. The overexpression of miR-326 or silencing of KLK7 was demonstrated to increase the content of DA, DOPAC, HVA, 3-MT, SOD, GSH-Px, and TH positive expression, while reducing iNOS positive expression, MDA content and cell apoptosis, as well as inhibited levels of IL-1, IL-6, TNF-α, INF-γ, and mRNA and protein levels of p38, ERK, JNK, and caspase-3. Taken together, these results provided evidence suggesting that miR-326 could inhibit iNOS activation and apoptosis of dopaminergic neurons through inhibiting the MAPK signaling pathway and negatively regulating KLK7 in mice with PD. These findings highlight the potential of miR-326 as a novel target for future PD treatment.

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
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Abbreviations

PD:

Parkinson’s disease

iNOS:

inducible nitric oxide synthase

HPLC:

high-performance liquid chromatography

DA:

dopamine

SOD:

superoxide dismutase

GSH-Px:

glutathione peroxidase

MDA:

malondialdehyde

TH:

tyrosine hydroxylase

KLK7:

kallikrein-related peptidase 7

DOPAC:

3,4-dihydroxyphenylacetic acid

3-MT:

3-methoxytyrosine

TUNEL:

terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling

HVA:

homovanillic acid

MAPK:

mitogen-activated protein kinase

ERK:

extracellular signal-regulated kinase

JNK:

c-Jun NH2-terminal protein kinase

3′UTR:

3′untranslated region

WT:

wild type

MUT:

mutant

PBS:

phosphate-buffered saline

FBS:

fetal bovine serum

RLU:

Ranilla luciferase

NC:

negative control

HBSS:

Hanks’ balanced salt solution

SPF:

specific pathogen-free

MPTP:

1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine

RT-qPCR:

reverse transcription quantitative polymerase chain reaction

IgG:

immunoglobulin G

DAB:

diaminobenzidine

OCT:

optimal cutting temperature

BSA:

bovine serum albumin

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

TRITC:

tetramethylrhodamine isothiocyanate

FITC:

fluorescein isothiocyanate

IL:

interleukin

ddH2O:

double distilled water

PVDF:

polyvinylidene fluoride

TBST:

tris-buffered saline Tween-20

ECL:

enhanced chemiluminescence

SD:

Sprague Dawley

References

  • Ashby EL, Kehoe PG, Love S (2010) Kallikrein-related peptidase 6 in Alzheimer’s disease and vascular dementia. Brain Res 1363:1–10

    Article  CAS  PubMed  Google Scholar 

  • Batra J, O’Mara T, Patnala R, Lose F, Clements JA (2012) Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases. Biol Chem 393(12):1365–1390

    Article  CAS  PubMed  Google Scholar 

  • Bellinger FP, Bellinger MT, Seale LA, Takemoto AS, Raman AV, Miki T, Manning-Bog AB, Berry MJ, White LR, Ross GW (2011) Glutathione peroxidase 4 is associated with neuromelanin in substantia nigra and dystrophic axons in putamen of Parkinson’s brain. Mol Neurodegener 6(1):8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Botella JA, Bayersdorfer F, Schneuwly S (2008) Superoxide dismutase overexpression protects dopaminergic neurons in a Drosophila model of Parkinson’s disease. Neurobiol Dis 30(1):65–73

    Article  CAS  PubMed  Google Scholar 

  • Briggs CE, Wang Y, Kong B, Woo TU, Iyer LK, Sonntag KC (2015) Midbrain dopamine neurons in Parkinson’s disease exhibit a dysregulated miRNA and target-gene network. Brain Res 1618:111–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calabresi P, Di Filippo M, Ghiglieri V, Tambasco N, Picconi B (2010) Levodopa-induced dyskinesias in patients with Parkinson’s disease: filling the bench-to-bedside gap. Lancet Neurol 9(11):1106–1117

    Article  CAS  PubMed  Google Scholar 

  • Chakraborty C, Sharma AR, Patra BC, Bhattacharya M, Sharma G, Lee SS (2016) MicroRNAs mediated regulation of MAPK signaling pathways in chronic myeloid leukemia. Oncotarget 7(27):42683–42697

    Article  PubMed  PubMed Central  Google Scholar 

  • Chaturvedi RK, Shukla S, Seth K, Agrawal AK (2006) Nerve growth factor increases survival of dopaminergic graft, rescue nigral dopaminergic neurons and restores functional deficits in rat model of Parkinson’s disease. Neurosci Lett 398(1–2):44–49

    Article  CAS  PubMed  Google Scholar 

  • Cho HJ, Liu G, Jin SM, Parisiadou L, Xie C, Yu J, Sun L, Ma B, Ding J, Vancraenenbroeck R, Lobbestael E, Baekelandt V, Taymans JM, He P, Troncoso JC, Shen Y, Cai H (2013) MicroRNA-205 regulates the expression of Parkinson’s disease-related leucine-rich repeat kinase 2 protein. Hum Mol Genet 22(3):608–620

    Article  CAS  PubMed  Google Scholar 

  • Choi I, Woo JH, Jou I, Joe EH (2016) PINK1 deficiency decreases expression levels of mir-326, mir-330, and mir-3099 during brain development and neural stem cell differentiation. Exp Neurobiol 25(1):14–23

    Article  PubMed  PubMed Central  Google Scholar 

  • Ci D, Song Y, Tian M, Zhang D (2015) Methylation of miRNA genes in the response to temperature stress in Populus simonii. Front Plant Sci 6:921

    Article  PubMed  PubMed Central  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(4):1161–1218

    Article  CAS  PubMed  Google Scholar 

  • Devetzi M, Trangas T, Scorilas A, Xynopoulos D, Talieri M (2013) Parallel overexpression and clinical significance of kallikrein-related peptidases 7 and 14 (KLK7KLK14) in colon cancer. Thromb Haemost 109(4):716–725

    Article  CAS  PubMed  Google Scholar 

  • Dong Y, Tan OL, Loessner D, Stephens C, Walpole C, Boyle GM, Parsons PG, Clements JA (2010) Kallikrein-related peptidase 7 promotes multicellular aggregation via the alpha(5)beta(1) integrin pathway and paclitaxel chemoresistance in serous epithelial ovarian carcinoma. Cancer Res 70(7):2624–2633

    Article  CAS  PubMed  Google Scholar 

  • Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, Beecham GW, Wang L, Zuchner S, Konidari I, Wang G, Singer C, Nahab F, Scott B, Stajich JM, Pericak-Vance M, Haines J, Vance JM, Martin ER (2010) Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 74(2):97–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feng G, Zhang Z, Bao Q, Zhang Z, Zhou L, Jiang J, Li S (2014) Protective effect of chinonin in MPTP-induced C57BL/6 mouse model of Parkinson’s disease. Biol Pharm Bull 37(8):1301–1307

    Article  CAS  PubMed  Google Scholar 

  • Gille G, Radad K, Reichmann H, Rausch WD (2006) Synergistic effect of alpha-dihydroergocryptine and L-dopa or dopamine on dopaminergic neurons in primary culture. J Neural Transm 113(9):1107–1118

    Article  CAS  PubMed  Google Scholar 

  • Guo Z, Shao L, Zheng L, Du Q, Li P, John B, Geller DA (2012) miRNA-939 regulates human inducible nitric oxide synthase posttranscriptional gene expression in human hepatocytes. Proc Natl Acad Sci U S A 109(15):5826–5831

    Article  PubMed  PubMed Central  Google Scholar 

  • Guo H, Qi RQ, Lv YN, Wang HX, Hong YX, Zheng S, Li JH, Gao XH, Chen HD (2016) miR-31 is distinctively overexpressed in primary male extramammary Paget’s disease. Oncotarget 7(17):24559–24563

    PubMed  PubMed Central  Google Scholar 

  • Hao B, Chen X, Dai D, Zou C, Wu X, Chen J (2015) Bioinformatic analysis of microRNA expression in Parkinson’s disease. Mol Med Rep 11(2):1079–1084

    Article  CAS  PubMed  Google Scholar 

  • Hebert SS, De Strooper B (2009) Alterations of the microRNA network cause neurodegenerative disease. Trends Neurosci 32(4):199–206

    Article  CAS  PubMed  Google Scholar 

  • Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79(4):368–376

    Article  CAS  Google Scholar 

  • Jha SK, Jha NK, Kar R, Ambasta RK, Kumar P (2015) p38 MAPK and PI3K/AKT signalling cascades in Parkinson’s disease. Int J Mol Cell Med 4(2):67–86

    CAS  PubMed  PubMed Central  Google Scholar 

  • Johnstone DM, el Massri N, Moro C, Spana S, Wang XS, Torres N, Chabrol C, De Jaeger X, Reinhart F, Purushothuman S, Benabid AL, Stone J, Mitrofanis J (2014) Indirect application of near infrared light induces neuroprotection in a mouse model of parkinsonism - an abscopal neuroprotective effect. Neuroscience 274:93–101

    Article  CAS  PubMed  Google Scholar 

  • Kefas B, Comeau L, Floyd DH, Seleverstov O, Godlewski J, Schmittgen T, Jiang J, diPierro CG, Li Y, Chiocca EA, Lee J, Fine H, Abounader R, Lawler S, Purow B (2009) The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors. J Neurosci 29(48):15161–15168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khasnavis S, Ghosh A, Roy A, Pahan K (2013) Castration induces Parkinson disease pathologies in young male mice via inducible nitric-oxide synthase. J Biol Chem 288(29):20843–20855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim EK, Choi EJ (2015) Compromised MAPK signaling in human diseases: an update. Arch Toxicol 89(6):867–882

    Article  CAS  PubMed  Google Scholar 

  • Kosik KS (2006) The neuronal microRNA system. Nat Rev Neurosci 7(12):911–920

    Article  CAS  PubMed  Google Scholar 

  • Lauretani F, Maggio M, Silvestrini C, Nardelli A, Saccavini M, Ceda GP (2012) Parkinson’s disease (PD) in the elderly: an example of geriatric syndrome (GS)? Arch Gerontol Geriatr 54(1):242–246

    Article  PubMed  Google Scholar 

  • Leal MC, Casabona JC, Puntel M, Pitossi FJ (2013) Interleukin-1beta and tumor necrosis factor-alpha: reliable targets for protective therapies in Parkinson’s disease? Front Cell Neurosci 7:53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li S, Lv X, Zhai K, Xu R, Zhang Y, Zhao S, Qin X, Yin L, Lou J (2016) MicroRNA-7 inhibits neuronal apoptosis in a cellular Parkinson’s disease model by targeting Bax and Sirt2. Am J Transl Res 8(2):993–1004

    CAS  PubMed  PubMed Central  Google Scholar 

  • Louter M, Tromp SC (2009) Parkinsonism due to the medication. Ned Tijdschr Geneeskd 153:A336

    PubMed  Google Scholar 

  • Martins M, Rosa A, Guedes LC, Fonseca BV, Gotovac K, Violante S, Mestre T, Coelho M, Rosa MM, Martin ER, Vance JM, Outeiro TF, Wang L, Borovecki F, Ferreira JJ, Oliveira SA (2011) Convergence of miRNA expression profiling, alpha-synuclein interacton and GWAS in Parkinson’s disease. PLoS One 6(10):e25443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muthian G, Mackey V, King J, Charlton CG (2010) Modeling a sensitization stage and a precipitation stage for Parkinson’s disease using prenatal and postnatal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Neuroscience 169(3):1085–1093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nie K, Zhang Y, Gan R, Wang L, Zhao J, Huang Z, Tang H, Wang L (2013) Polymorphisms in immune/inflammatory cytokine genes are related to Parkinson’s disease with cognitive impairment in the Han Chinese population. Neurosci Lett 541:111–115

    Article  CAS  PubMed  Google Scholar 

  • Pramanik D, Campbell NR, Karikari C, Chivukula R, Kent OA, Mendell JT, Maitra A (2011) Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice. Mol Cancer Ther 10(8):1470–1480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saito T, Nakanishi H, Mochizuki Y, Ito S, Ito Y, Misawa K, Yatabe Y, Yamamichi K, Kondo E (2015) Preferential HER2 expression in liver metastases and EGFR expression in peritoneal metastases in patients with advanced gastric cancer. Gastric Cancer 18(4):711–719

    Article  CAS  PubMed  Google Scholar 

  • Scalzo P, Kummer A, Cardoso F, Teixeira AL (2009) Increased serum levels of soluble tumor necrosis factor-alpha receptor-1 in patients with Parkinson’s disease. J Neuroimmunol 216(1–2):122–125

    Article  CAS  PubMed  Google Scholar 

  • Scalzo P, Kummer A, Cardoso F, Teixeira AL (2010) Serum levels of interleukin-6 are elevated in patients with Parkinson’s disease and correlate with physical performance. Neurosci Lett 468(1):56–58

    Article  CAS  PubMed  Google Scholar 

  • Sukumar N, Scott E, Dimitromanolakis A, Misiak A, Prassas I, Diamandis EP, Konvalinka A (2014) Mining for single nucleotide variants (SNVs) at the kallikrein locus with predicted functional consequences. Biol Chem 395(9):1037–1050

    Article  CAS  PubMed  Google Scholar 

  • Thome AD, Harms AS, Volpicelli-Daley LA, Standaert DG (2016) microRNA-155 regulates alpha-synuclein-induced inflammatory responses in models of Parkinson disease. J Neurosci 36(8):2383–2390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walker F, Nicole P, Jallane A, Soosaipillai A, Mosbach V, Oikonomopoulou K, Diamandis EP, Magdolen V, Darmoul D (2014) Kallikrein-related peptidase 7 (KLK7) is a proliferative factor that is aberrantly expressed in human colon cancer. Biol Chem 395(9):1075–1086

    Article  CAS  PubMed  Google Scholar 

  • Wu D, Tseng IJ, Yuan RY, Hsieh CY, Hu CJ (2014) Memory consolidation and inducible nitric oxide synthase expression during different sleep stages in Parkinson disease. Sleep Med 15(1):116–120

    Article  PubMed  Google Scholar 

  • Xia D, Tian S, Chen Z, Qin W, Liu Q (2018) miR302a inhibits the proliferation of esophageal cancer cells through the MAPK and PI3K/Akt signaling pathways. Oncol Lett 15(3):3937–3943

    PubMed  PubMed Central  Google Scholar 

  • Xiao L, Zhou X, Liu F, Hu C, Zhu X, Luo Y, Wang M, Xu X, Yang S, Kanwar YS, Sun L (2015) MicroRNA-129-5p modulates epithelial-to-mesenchymal transition by targeting SIP1 and SOX4 during peritoneal dialysis. Lab Investig 95(7):817–832

    Article  CAS  PubMed  Google Scholar 

  • Xie XX, Kou ST, Pu ZH, Hou CY, Tian YP (2007) Effects of scalp catgut embedding on SOD, NO, MDA in the rat with Parkinson’s disease. Zhongguo zhen jiu = Chin Acupunct moxibust 27(10):753–756

    CAS  Google Scholar 

  • Xie YF, Shu R, Jiang SY, Liu DL, Ni J, Zhang XL (2013) MicroRNA-146 inhibits pro-inflammatory cytokine secretion through IL-1 receptor-associated kinase 1 in human gingival fibroblasts. J Inflamm 10(1):20

    Article  CAS  Google Scholar 

  • Yin XF, Xu HM, Jiang YX, Zhi YL, Liu YX, Xiang HW, Liu K, Ding XD, Sun P (2015) Lentivirus-mediated Persephin over-expression in Parkinson’s disease rats. Neural Regen Res 10(11):1814–1818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoon H, Blaber SI, Li W, Scarisbrick IA, Blaber M (2013) Activation profiles of human kallikrein-related peptidases by matrix metalloproteinases. Biol Chem 394(1):137–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu SY, Zuo LJ, Wang F, Chen ZJ, Hu Y, Wang YJ, Wang XM, Zhang W (2014) Potential biomarkers relating pathological proteins, neuroinflammatory factors and free radicals in PD patients with cognitive impairment: a cross-sectional study. BMC Neurol 14:113

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang Z, Luo X, Ding S, Chen J, Chen T, Chen X, Zha H, Yao L, He X, Peng H (2012) MicroRNA-451 regulates p38 MAPK signaling by targeting of Ywhaz and suppresses the mesangial hypertrophy in early diabetic nephropathy. FEBS Lett 586(1):20–26

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Li S, Yan Q, Chen X, Yang Y, Liu X, Wan X (2013) Interferon-beta induced microRNA-129-5p down-regulates HPV-18 E6 and E7 viral gene expression by targeting SP1 in cervical cancer cells. PLoS One 8(12):e81366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Q, Chen J, Yi S, Lou Y, Tang W, Liu Y, Zhang P (2012) Zhichan powder regulates nigrostriatal dopamine synthesis and metabolism in Parkinson’s disease rats. Neural Regen Res 7(27):2107–2114

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ziebarth JD, Bhattacharya A, Cui Y (2012) Integrative analysis of somatic mutations altering microRNA targeting in cancer genomes. PLoS One 7(10):e47137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We would like to acknowledge the helpful comments on this paper received from our reviewers.

Author information

Authors and Affiliations

  1. Department of Neurology, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, People’s Republic of China

    Yizhi Zhang, Weiwei Xu, Shanji Nan & Jia Fan

  2. Department of Neurology, Changchun Central Hospital, Changchun, 130000, People’s Republic of China

    Meiji Chang

Authors
  1. Yizhi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weiwei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shanji Nan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meiji Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jia Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jia Fan.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

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

Yizhi Zhang and Weiwei Xu are co-first authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Xu, W., Nan, S. et al. MicroRNA-326 Inhibits Apoptosis and Promotes Proliferation of Dopaminergic Neurons in Parkinson’s Disease Through Suppression of KLK7-Mediated MAPK Signaling Pathway. J Mol Neurosci 69, 197–214 (2019). https://doi.org/10.1007/s12031-019-01349-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-019-01349-1

Keywords

Search

Navigation