| Summary: | <p>Dysregulation of microRNA gene expression has been implicated in many neurodegenerative diseases, including Parkinson’s disease. However, the individual dysregulated microRNAs remain largely unknown. Previous meta-analyses have highlighted several microRNAs being differentially expressed in post-mortem Parkinson’s disease and Alzheimer's disease brains versus controls, but they were based on small sample sizes. In this study, we quantified the expression of the most compelling Parkinson’s and Alzheimer’s disease microRNAs from these meta-analyses (‘candidate miRNAs’) in one of the largest Parkinson’s/Alzheimer’s disease case–control post-mortem brain collections available (<em>n</em> = 451), thereby quadruplicating previously investigated sample sizes. Parkinson’s disease candidate microRNA hsa-miR-132-3p was differentially expressed in our Parkinson’s (<em>P</em> = 4.89E−06) and Alzheimer’s disease samples (<em>P</em> = 3.20E−24) compared with controls. Alzheimer’s disease candidate microRNAs hsa-miR-132-5p (<em>P</em> = 4.52E−06) and hsa-miR-129-5p (<em>P</em> = 0.0379) were differentially expressed in our Parkinson’s disease samples. Combining these novel data with previously published data substantially improved the statistical support (α = 3.85E−03) of the corresponding meta-analyses, clearly implicating these microRNAs in both Parkinson’s and Alzheimer’s disease. Furthermore, hsa-miR-132-3p/-5p (but not hsa-miR-129-5p) showed association with α-synuclein neuropathological Braak staging (<em>P</em> = 3.51E−03/<em>P</em> = 0.0117), suggesting that hsa-miR-132-3p/-5p play a role in α-synuclein aggregation beyond the early disease phase. Our study represents the largest independent assessment of recently highlighted candidate microRNAs in Parkinson’s and Alzheimer’s disease brains, to date. Our results implicate hsa-miR-132-3p/-5p and hsa-miR-129-5p to be differentially expressed in both Parkinson’s and Alzheimer’s disease, pinpointing shared pathogenic mechanisms across these neurodegenerative diseases. Intriguingly, based on publicly available high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation data, hsa-miR-132 may interact with <em>SNCA</em> messenger RNA in the human brain, possibly pinpointing novel therapeutic approaches in fighting Parkinson’s disease.</p>
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