Galectin-9 activates microglial asparagine endopeptidase and promotes α-synuclein pathology in Parkinson's disease

Area of Science:

• Neuroscience
• Immunology
• Molecular Biology

Background:

• Parkinson's disease (PD) involves alpha-synuclein (α-syn) aggregation and microglial activation.
• Galectin-9 (Gal-9) is a microglial mediator with immunoregulatory functions.

Purpose of the Study:

• To investigate the role of Gal-9 in α-syn processing and neurodegeneration in PD.
• To elucidate the molecular mechanisms linking Gal-9, α-syn, and microglial activation.

Main Methods:

• Utilized cell cultures and a mouse model of PD induced by α-syn pre-formed fibrils (PFFs).
• Investigated the effects of Gal-9 knockout and AEP protease activity on α-syn pathology and neurotoxicity.
• Analyzed the C/EBPβ/AEP signaling axis in response to α-syn fibril uptake by microglia.

Main Results:

• Microglial uptake of α-syn fibrils leads to increased Gal-9 expression.
• Gal-9 promotes toxic α-syn species production via the C/EBPβ/AEP axis.
• Gal-9 knockout attenuated α-syn pathology, neuronal loss, and motor deficits in a PD mouse model.
• AEP knockout mitigated the detrimental effects of Gal-9 in PD models.

Conclusions:

• Galectin-9 plays a critical role in promoting α-syn pathology and neurodegeneration in Parkinson's disease.
• The C/EBPβ/AEP signaling pathway is a key mediator of Gal-9's detrimental effects.
• Targeting Gal-9 or AEP presents a potential therapeutic avenue for PD.