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

Area of Science:

• Neuroscience
• Genetics
• Immunology

Background:

• Parkinson's disease (PD) is a prevalent neurodegenerative disorder with incompletely understood pathogenesis.
• Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene are a major genetic cause of PD.
• Mitochondrial dysfunction and neuroinflammation are implicated in LRRK2-associated PD, but molecular mechanisms are unclear.

Purpose of the Study:

• To investigate the effects of mutant LRRK2-R1441G and MPP+ on microglial activation and gene expression.
• To elucidate the molecular mechanisms underlying LRRK2-mediated neuroinflammation in PD.

Main Methods:

• Utilized a human microglial cell line (HMC-3).
• Applied RNA sequencing and biological assays to analyze gene and pathway changes.
• Investigated the impact of LRRK2 kinase inhibitors and miR-146a-5p modulation.

Main Results:

• Mutant LRRK2-R1441G with MPP+ induced M1 microglial activation by activating interferon signaling and reducing miR-146a-5p.
• This led to increased Stat1 and decreased Nrf2 levels, promoting neuroinflammation.
• LRRK2 inhibition or miR-146a-5p restoration shifted microglia to M2, reducing neuroinflammation by normalizing interferon signaling and Nrf2 levels.

Conclusions:

• LRRK2 regulates microglial activation and neuroinflammation in PD pathogenesis.
• Targeting LRRK2 kinase or modulating miR-146a-5p are potential therapeutic strategies for PD.
• These strategies may also benefit other LRRK2-linked neuroinflammatory disorders.