A Conserved MicroRNAs Motif Reveals TDP ‐43 Pathology and MAPK Pathway Activation in Parkinson's Disease

ABSTRACT Parkinson's disease (PD), the second most common neurodegenerative disorder, involves dopaminergic neuron loss and α‐synuclein (α‐syn) aggregation. Recent studies have shown that dysregulation of microRNAs (miRNAs) is associated with PD, but little is known about its pathological mechanism. Here, we identified a conserved 5‐nucleotide motif (HBCCC; H = U, A, or C; B = U, C, or G) in 52 downregulated miRNAs from the salivary RT‐QuIC (real‐time quaking‐induced conversion)‐positive PD patients, accounting for 82.5% of these dysregulated miRNAs. The motif‐containing miRNAs, including miRNA‐6812‐3p and miRNA‐6848‐3p, were also significantly downregulated in the substantia nigra of PD patients. Quantitative Real‐Time PCR (RT‐qPCR), miRNA pull‐down assay, and western blot confirmed that TAR DNA binding protein‐43 (TDP‐43) bound to the motif‐containing miRNAs in vitro and was responsible for the biogenesis of these miRNAs. Furthermore, we found that TDP‐43 co‐aggregated with α‐syn in vitro and in vivo, which could be responsible for the downregulation of miRNAs. Motif‐containing miRNAs targeted the mitogen‐activated protein kinase (MAPK) pathway, and their downregulation in PD activated this pathway, as revealed by bioinformatic analysis. Interfering with MAPK expression alleviated movement disorders in a Drosophila PD model. These findings provide a potential therapeutic target for PD and highlight the pathological role of miRNAs in neurodegenerative diseases.