Aberrant Expression of Circulating MicroRNA Leads to the Dysregulation of Alpha-Synuclein and Other Pathogenic Genes in Parkinson’s Disease

Abstract

A group of circulating microRNAs (miRNAs) have been implicated in the pathogenesis of Parkinson’s disease. However, a comprehensive study of the interactions between pathogenic miRNAs and their downstream Parkinson’s disease (PD)-related target genes has not been performed. Here, we identified the miRNA expression profiles in the plasma and circulating exosomes of Parkinson’s disease patients using next-generation RNA sequencing. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses showed that the miRNA target genes were enriched in axon guidance, neurotrophin signaling, cellular senescence, and the Transforming growth factor-β (TGF-β), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) signaling pathways. Furthermore, a group of aberrantly expressed miRNAs were selected and further validated in individual patient plasma, human neural stem cells (NSCs) and a rat model of PD. More importantly, the full scope of the regulatory network between these miRNAs and their PD-related gene targets in human neural stem cells was examined, and the findings revealed a similar but still varied downstream regulatory cascade involving many known PD-associated genes. Additionally, miR-23b-3p was identified as a novel direct regulator of alpha-synuclein, which is possibly the key component in PD. Our current study, for the first time, provides a glimpse into the regulatory network of pathogenic miRNAs and their PD-related gene targets in PD. Moreover, these PD-associated miRNAs may serve as biomarkers and novel therapeutic targets for PD.

Small but Mighty—Exosomes, Novel Intercellular Messengers in Neurodegeneration

“…A number of studies examined microRNAs packaged in exosomes from cerebrospinal fluid and plasma of Parkinson's disease patients, cultured cells, and rat models of Parkinson's disease [233][234][235][236]. Several microRNAs were differentially associated with exosomes from the diseased samples as compared to controls.…”

“…MicroRNA-23b-3p binds to 3 -untranslated region of α-synuclein. Reduction of miR-23b-3p in exosomes leads to upregulation of α-synuclein mRNA [235], thereby increasing expression of α-synuclein protein in Parkinson's disease. The underlying cause of Parkinson's disease is not only an increase in α-synuclein but a combination of several dysregulated pathways that lead to etiology of the disease.…”

Dysregulated miRNAs as Biomarkers and Therapeutical Targets in Neurodegenerative Diseases

“…Dysregulation of miRNA expression profiles has been described in several brain areas and fluids of PD patients, as well as in iPSCs-derived DNs generated from affected patients. Table 2 shows a list of 15 miRNAs (let-7b, miR-34b, miR-124, miR-126, miR-132, miR-133b, miR-144, miR-148b, miR-184, miR-199a, miR-204, miR-218, miR-221, miR-338, miR-425) that were found dysregulated by at least two independent studies in nervous tissues (midbrain, prefrontal cortex, amygdala, laser-micro dissected DNs, or anterior cingulate gyrus) [ 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 ], iPSC-derived DNs [ 119 ] and circulating fluids (CSF, plasma, serum, peripheral blood) [ 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 ] of PD patients, thus supporting their potential utility as biomarkers and/or therapeutic targets.…”

“…The following PD-specific miRNAs have been reported as potential diagnostic biomarkers in circulating fluids: miR-126 [ 122 ], miR-144 [ 124 ], miR-184 [ 145 ], miR-204 [ 127 ] and miR-221 [ 120 , 128 , 129 , 130 ]. Among them, miR-144 has been proposed as an early biomarker [ 123 ].…”

“…In PD models, miR-218 plays a role in modulating the NF-κB inflammatory signaling pathway, by influencing the activity of three importins, KPNB1, KPNA3, and KPNA4 [ 107 ], and interacts with the PD related gene PRKN [ 269 ], leading to mitochondrial dysfunction through the autophagic pathway [ 188 ] ( Table 2 , Figure 2 ). In addition, altered levels of miR-218 were found in brain regions and blood of PD patients [ 145 ] and were also associated with therapeutic brain stimulation [ 134 , 135 ] ( Table 2 ). Dysregulation of miR-218 was also observed in ALS patients and animal models [ 212 , 229 , 248 , 251 ] ( Table 3 ).…”