USP18 is a key regulator of immune function in mouse midbrain microglia

Area of Science:

• Neuroscience
• Immunology
• Molecular Biology

Background:

• Ubiquitin-specific peptidase 18 (USP18) is a deubiquitinating enzyme crucial for regulating immune responses, particularly in microglia.
• USP18's specific role in midbrain immune regulation and its molecular mechanisms remain incompletely understood.

Purpose of the Study:

• To investigate the function of USP18 in the midbrain.
• To elucidate the molecular mechanisms underlying USP18's role in midbrain immune activity and neuroprotection.

Main Methods:

• Developed a midbrain-specific USP18 high-expression mouse model using adeno-associated virus (AAV) vectors.
• Conducted multi-omics analysis including RNA sequencing and untargeted metabolomics.
• Assessed protein expression via Western blot and quantified neuroinflammatory factors using ELISA.

Main Results:

• USP18 acts as a key regulator of midbrain immune activity, maintaining microglia in a resting state and promoting neuroprotection via TH protein expression.
• USP18 deficiency led to altered neuroimmune responses, inflammation-associated gene expression, and metabolite profiles, with significant enrichment of the TLR signaling pathway.
• Loss of USP18 increased TLR2, Iba-1, and GFAP protein levels while decreasing TH levels, particularly in microglia, mirroring changes seen in human neurodegenerative diseases.

Conclusions:

• USP18 critically regulates midbrain microglia and neuroinflammation by modulating TLR2 protein levels.
• Findings offer novel insights into neurodegenerative disease mechanisms and potential therapeutic targets.