Regulation of α-synuclein homeostasis and inflammasome activation by microglial autophagy

Abstract

Autophagy clears protein aggregates, damaged cellular organelles, and pathogens through the lysosome. Although autophagy is highly conserved across all cell types, its activity in each cell is specifically adapted to carry out distinct physiological functions. The role of autophagy in neurons has been well characterized; however, in glial cells, its function remains largely unknown. Microglia are brain-resident macrophages that survey the brain to remove injured neurons, excessive synapses, protein aggregates, and infectious agents. Current studies have demonstrated that dysfunctional microglia contribute to neurodegenerative diseases. In Alzheimer's disease animal models, microglia play a critical role in regulating amyloid plaque formation and neurotoxicity. However, how microglia are involved in Parkinson's disease (PD) remains poorly understood. Propagation of aggregated α-synuclein via cell-to-cell transmission and neuroinflammation have emerged as important mechanisms underlying neuropathologies in PD. Here, we review converging evidence that microglial autophagy maintains α-synuclein homeostasis, regulates neuroinflammation, and confers neuroprotection in PD experimental models.

Fig. 1.. The neuroprotective function of microglial autophagy in the clearance of α-synuclein and inflammasome regulation.

(Left) The neuroprotective function of microglial autophagy in the clearance of α-synuclein and inflammasome regulation. α-Synuclein activates the NF-κB pathway through TLR2 and TLR4 and increases the level of p62 mRNA. As a selective autophagy receptor, p62 binds to internalized α-synuclein and recruits autophagy machinery. The p62–α-synuclein complex is sequestered by autophagosome and degraded by lysosome. (Right) Activated NF-κB pathway by TLR–α-synuclein interaction increases the level of NLRP3 mRNA, priming the activation of inflammasome. Components of the inflammasome complex are recognized by autophagy machinery and degraded by autophagosome-lysosome, preventing the excessive formation of the inflammasome in the brain.