The Interferon-miR-146a-5p-Stat1/Nrf2 Pathway Mediates LRRK2-R1441G-induced M1 over M2 Microglia Activation

Parkinson's disease (PD) is the second most common neurodegenerative disease with movement disorder. The etiology and molecular pathogenesis of PD are not fully understood. Mutations in the LRRK2 gene are the primary genetic causes of PD and contribute to sporadic PD. Mitochondrial dysfunction and neuroinflammation have been reported in LRRK2-based PD models. However, the molecular mechanisms in LRRK2-linked PD remain largely unknown. In this study, we used a human microglial cell line (HMC-3) to study the effects of mutant LRRK2-R1441G and a mitochondrial toxin (MPP⁺), on microglial activation and its linked gene and pathway changes using RNA sequencing combined with biological assays. We found that mutant LRRK2-R1441G with MPP⁺ exposure induced M1 rather than M2 microglial activation by activating the interferon signaling pathway and reducing miR-146a-5p function thereby elevating its targeted genes, such as Stat1, and reducing Nrf2 levels to inhibit neuroinflammation. Whereas treatment of LRRK2 kinase inhibitor or elevated miR-146a-5p could promote the shift of microglia from M1 to M2 activation by correcting interferon signaling and/or restoring the miR-146a-5p levels, reducing Stat1 and increasing Nrf2 levels thereby inhibiting neuroinflammation. Our findings not only provide novel insights into the mechanisms of LRRK2 regulating microglial activation underlying neuroinflammation in PD pathogenesis but also validate that targeting LRRK2 and/or miR-146a-5p could be potential novel treatment strategies for PD and other LRRK2-linked neuroinflammatory disorders.