Abstract
This study aimed to screen the target miRNAs and to investigate the differential miR-3557/324-targeted signal mechanisms in the rats' model of Parkinson's disease (PD) with regular aerobic exercise. Rats were divided into sedentary control PD group (SED-PD, n = 18) and aerobic exercise PD group (EX-PD, n = 22). After 8 weeks of regular aerobic exercise, a 6-hydroxydopamine- (6-OHDA-) induced PD lesion model was constructed. Preregular aerobic exercises enhanced the injury resistance of rats with 6-OHDA-induced PD. The rotational behavior after injection of apomorphine hydrochloride was alleviated. Under the scanning electron microscopy, we found the neurons, axons, and villi of the striatum were clearly and tightly arranged, and neurons and axons significantly becoming larger. Tyrosine hydroxylase (TH) was increased significantly and α-synuclein protein expression was reduced in the EX-PD group compared to the SED-PD group. Screening from miRNA microarray chip, we further found upregulation of miR-3557 and downregulation of miR-324 were closely related to the calcium-modulating signaling pathway, remitting the progress of Parkinson's disease on aerobic exercise. Compared to the SED-PD group, Ca2+/calmodulin dependent protein kinase II (CaMK2α) was upregulated, but CaMKV and voltage-dependent anion-selective channel protein 1 (Vdac1) were significantly downregulated in the EX-PD group. Additionally, phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) expression were activated, and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) expression was upregulated in the EX-PD group. Conclusions: the adaptive mechanism of regular aerobic exercise delaying neurodegenerative diseases and lesions was that miR-3557/324 was activated to regulate one of its targets CaMKs signaling pathways. CaMKs, coordinated with mTOR pathway-related gene expression, improved UCH-L1 level to favor for delaying neurodegeneration or improving the pathogenesis of PD lesions.
Highlights
MicroRNAs are associated with various diseases, such as neurodegenerative diseases [Alzheimer’s disease (AD), Parkinson’s disease (PD), and Schizophrenia][1], cardiovascular diseases [2], and metabolic diseases [3]
Packer et al [9] found that the expression of miR-9 decreased in patients with PD patients, which might be involved in the pathogenesis of PD by modulating the target gene RE1-Silencing Transcription factor (REST)/coREST. miR-133 regulated the expression of transcription factor N-myc downregulated gene 1 (NGRG1) associated with PD; miR-7, miR-153, and miR433 regulated the expression of α-synuclein in PD [10]
We found the adaptive mechanism of regular aerobic exercise delaying the development of neurodegenerative diseases and lesions was to initiate miR-3557 and miR-324 to regulate one of its target Ca2+/calmodulin dependent protein kinase (CaMKs) signaling pathways and to coordinate with regulating closely related phosphatidylinositol-3-kinase (PI3K)/ protein kinase B(Akt) /mammalian target of rapamycin pathway protein expression, delaying the progression of neurodegeneration or alleviating the development of PD lesions
Summary
MicroRNAs (miRNAs or miR) are associated with various diseases, such as neurodegenerative diseases [Alzheimer’s disease (AD), Parkinson’s disease (PD), and Schizophrenia][1], cardiovascular diseases (myocardial infarction, myocardial fibrosis, and atherosclerosis) [2], and metabolic diseases (diabetes and obesity) [3]. MicroRNAs (miRNAs or miR) are associated with various diseases, such as neurodegenerative diseases [Alzheimer’s disease (AD), Parkinson’s disease (PD), and Schizophrenia]. MiRNAs were rich in brain tissues (such as miR-125b) and important in the regulation of gene expression in different physiological processes and signaling pathways of the nervous system, such as the development and progression of the nervous system, neural stem cell differentiation, and apoptosis [4]. Lemaitre et al [8] showed that the expression of miR433 decreased and the expression of fibroblast growth factor 20 (FGF20) increased in patients with PD, while FGF20 promoted the expression of α-synuclein, which is the most critical protein in PD pathogenesis. Packer et al [9] found that the expression of miR-9 decreased in patients with PD patients, which might be involved in the pathogenesis of PD by modulating the target gene RE1-Silencing Transcription factor (REST)/coREST. Dostie et al [11] showed that miR-175 was associated with early clinical manifestations of PD. miR-132 and miR-212 were involved in the occurrence of various abnormalities, such as synaptic plasticity and connectivity in schizophrenia [12]
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