Association of Glial Activation and α-Synuclein Pathology in Parkinson's Disease

Abstract

The accumulation of pathological α-synuclein (α-syn) in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta are the neuropathological features of Parkinson's disease (PD). Recently, the findings of prion-like transmission of α-syn pathology have expanded our understanding of the region-specific distribution of α-syn in PD patients. Accumulating evidence suggests that α-syn aggregates are released from neurons and endocytosed by glial cells, which contributes to the clearance of α-syn. However, the activation of glial cells by α-syn species produces pro-inflammatory factors that decrease the uptake of α-syn aggregates by glial cells and promote the transmission of α-syn between neurons, which promotes the spread of α-syn pathology. In this article, we provide an overview of current knowledge on the role of glia and α-syn pathology in PD pathogenesis, highlighting the relationships between glial responses and the spread of α-syn pathology.

Keywords: Astrocyte activation; Microglial activation; Neuroinflammation; Parkinson's disease; α-synuclein pathology.

Fig. 1

Schematic of the impact of α-syn aggregates on the activation of microglia and astrocytes and their contributions to α-syn pathology. α-Syn aggregates propagate between neurons and are released from them. Extracellular α-syn aggregates activate microglia by initiating the NF-κB-dependent inflammatory response and inflammasome activation via pattern recognition receptors (PPRs) or Fyn. Extracellular α-syn aggregates induce the NF-κB-dependent inflammatory response in astrocytes, and this is associated with the activation of RIPK signaling. Meanwhile, microglia phagocytose extracellular α-syn aggregates and transport them to lysosomes for degradation. Overloaded α-syn in microglia or astrocytes can be transmitted between microglia through cellular networks or between astrocytes through tunneling nanotubes (TNTs). In addition, microglia and astrocytes activated by α-syn aggregates produce pro-inflammatory factors, which damage neurons and promote the transmission of α-syn pathology between neurons.

Fig. 2

Schematic of the interactions among glial activation, α-syn pathology, and neurodegeneration in PD. α-Syn pathology leads to the activation of glia, which contributes to α-syn pathology. Neurodegeneration occurs due to either the direct neurotoxicity of α-syn aggregates or the release of pro-inflammatory factors by the activated glia. In addition, glial activation and α-syn aggregation as well as aging lead to a decrease in phagocytosis by glial cells, resulting in an accelerated spread of α-syn pathology.