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

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.