MicroRNA-212-5p Prevents Dopaminergic Neuron Death by Inhibiting SIRT2 in MPTP-Induced Mouse Model of Parkinson’s Disease

Frontiers in Molecular Neuroscience

Sifan Sun¹  Miaomiao Jia²  Qiqi Song²  Xueting Li²  Xiaojuan Han³  Gang Hu⁴  Ming Lu⁴  Jianhua Ding⁴ 

[1] Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China;Department of Pharmacology, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, China;Department of Traditional Chinese Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China;Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China;

关键词: miR-212-5p;    SIRT2;    p53;    autophagy;    apoptosis;    Parkinson’s disease;   

DOI  :  10.3389/fnmol.2018.00381

来源: DOAJ

【 摘 要 】

Recently, emerging evidences show that sirtuins (SIRTs) modulate aging progress and affect neurodegenerative diseases. For example, inhibition of SIRT2 has been recognized to exert neuroprotective effects in Parkinson’s disease (PD). However, current SIRT2 inhibitors are lack of selective property distinguished from its homolog. In this study, we found that SIRT2 protein level was highly increased in PD model, which was negatively regulated by miR-212-5p. In detail, miR-212-5p transfection reduced SIRT2 expression and inhibited SIRT2 activity. In vivo study, miR-212-5p treatment prevented dopaminergic neuron loss and DAT reduction by targeting SIRT2, which means miR-212-5p shows neuroprotective effect in PD. Mechanismly, we found nuclear acetylated p53 was up-regulation according to p53 is a major deacetylation substrate of SIRT2. Furthermore, decreased cytoplasmic p53 promoted autophagy in PD model, which was showed as autophagosomes, autophagic flux, LC3 B and p62 expression. Meanwhile, we also found miR-212-5p treatment somehow alleviated apoptosis in PD model, which might have some underlying mechanisms. In conclusions, our study provides a direct link between miR-212-5p and SIRT2-mediated p53-dependent programmed cell death in the pathogenesis of PD. These findings will give us an insight into the development of highly specifically SIRT2 inhibitor of opening up novel therapeutic avenues for PD.

【 授权许可】

Unknown