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MicroRNAs (miRNAs) are extensively edited in human brains. However, the functional relevance of the miRNA editome is largely unknown in Parkinson's disease (PD). By analyzing small RNA sequencing profiles of brain tissues of 43 PD patients and 88 normal controls, we found that the editing levels of five A-to-I and two C-to-U editing sites are significantly correlated with the ages of normal controls, which is disrupted in PD patients. We totally identified 362 miRNA editing sites with significantly different editing levels in prefrontal cortices of PD patients (PD-PC) compared to results of normal controls. We experimentally validated that A-to-I edited miR-497-5p, with significantly higher expression levels in PD-PC compared to normal controls, directly represses OPA1 and VAPB. Furthermore, overexpression of A-to-I edited miR-497-5p downregulates OPA1 and VAPB in two cell lines, and inhibits proliferation of glioma cells. These results suggest that the hyperediting of miR-497-5p in PD contributes to enhanced progressive neurodegeneration of PD patients. Our results provide new insights into the mechanistic understanding, novel diagnostics, and therapeutic clues of PD. [ABSTRACT FROM AUTHOR]