Modified level of miR‐376a is associated with Parkinson's disease

Abstract

Parkinson's disease (PD) is a frequent progressive neurodegenerative disorder. Impaired mitochondrial function is a major feature of sporadic PD. Some susceptibility or causative genes detected in PD are strongly associated with mitochondrial dysfunction including PGC1α, TFAM and GSK3β. microRNAs (miRNAs) are non‐coding RNAs whose altered levels are proven in disparate PD models and human brains. Therefore, the aim of this study was to detect modulations of miRs upstream of PGC1α, TFAM and GSK3β in association with PD onset and progress. In this study, a total of 33 PD subjects and 25 healthy volunteers were recruited. Candidate miRNA (miR‐376a) was selected through target prediction tools and literature survey. Chronic and acute in vitro PD models were created by MPP+‐intoxicated SHSY5Y cells. The levels of miR‐376a and aforementioned genes were assessed by RT‐qPCR. The expression of target genes was decreased in chronic model while there were dramatically up‐regulated levels of those genes in acute model of PD. miR‐376a was strongly altered in both acute and chronic PD models as well as PBMCs of PD patients. Our results also showed overexpression of PGC1α, and TFAM in PBMCs is inversely correlated with down‐regulation of miR‐376a, suggesting that miR‐376a possibly has an impact on PD pathogenesis through regulation of these genes which are involved in mitochondrial function. miR‐376a expression in PD‐derived PBMCs was also correlated with disease severity and may serve as a potential biomarker for PD diagnosis. This is the first study showing altered levels of miR‐376a in PD models and PBMCs, suggesting the probable role of this miRNA in PD pathogenesis. The present study also proposed TFAM and PGC1α as target genes of miR‐376a for the first time, through which it possibly can exert its impact on PD pathogenesis.

MiR‐193b deregulation is associated with Parkinson's disease

“…Thus, we made use of MPP+ to induce neurotoxicity in cultured neuronal cells, to construct both acute and chronic in vitro PD models. Previous studies have shown that oxidative stress and apoptotic pathways are two principal mechanisms of MPP+‐induced cell death 2 , 19,20 . Consistently, here, treatment of SH‐SY5Y neuronal cells with 2000 µM MPP+ for 24 hours and 1000 µM over 2 weeks remarkably increased the percentage of apoptotic cells and ROS generation, confirming that complex 1 has been blocked efficiently by MPP+ in both models of PD in our study.…”

“…Growing evidence also represents that there is a correspondence between peripheral blood and brain tissue, suggesting that evaluating disease‐relevant genes’ expression in peripheral blood can act as an advantageous proxy measure for gene expression in the CNS and reflect the state of illness in the brain 37 . PBMCs are deemed to be a peripheral laboratory providing a golden opportunity to study the mechanisms linked to NDDs and to find an indicator for their prognosis, diagnosis and treatment 12 , 19 . Accordingly, here, cell models of PD were developed to clarify whether miR‐193b and PGC‐1α/FNDC5/BDNF pathway are affected by oxidative stress.…”

“…MicroRNAs (miR(NA)s) are highly conserved endogenous small (~22 nucleotide) non‐coding RNAs that control gene expression at the post‐transcriptional level by binding to the 3' UTRs of mRNAs. 2 , 19,20 Multiple lines of evidence confirmed an essential role of miRNAs in neuronal survival and normal function 21,22 . miRNAs participate extensively in a number of neurodegenerative processes like PD and their dysregulation has been observed in several PD models and post‐mortem human brain tissues, resulting in their being introduced as attractive therapeutic targets or biomarkers for PD 2 , 20 , 21 , 23 , 24 …”

Epigenetic Regulation of Neuroinflammation in Parkinson’s Disease

“…MicroRNAs belongs to the class of small non-coding RNA (sncRNA) with a length of 17–22 nt. They inhibit gene expression level by binding to the 3’untranslated region (3’UTR) of mRNA, resulting in mRNA degradation, adenylation, or translational inhibition [ 39 ]. Over the past few years, various miRNAs target PD-related genes that induce neuroinflammation and accelerate the neurodegeneration of dopaminergic neurons ( Table 1 ).…”

Non-Coding RNAs in the Brain-Heart Axis: The Case of Parkinson’s Disease

“… Role of microRNAs in Parkinson’s disease [ 28 , 52 , 54 , 63 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ]. …”