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Journal of Molecular Neuroscience

, Volume 69, Issue 2, pp 197–214 | Cite as

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

  • Yizhi Zhang
  • Weiwei Xu
  • Shanji Nan
  • Meiji Chang
  • Jia FanEmail author
Article

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.

Keywords

Parkinson’s disease microRNA-326 Kallikrein-related peptidase 7 Mitogen-activated protein kinase signaling pathway Inducible nitric oxide synthase Apoptosis 

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

Notes

Acknowledgments

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

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurologyThe Second Hospital of Jilin UniversityChangchunPeople’s Republic of China
  2. 2.Department of NeurologyChangchun Central HospitalChangchunPeople’s Republic of China

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