Extracellular Alpha-Synuclein: Mechanisms for Glial Cell Internalization and Activation

Abstract

Alpha-synuclein (α-syn) is a small protein composed of 140 amino acids and belongs to the group of intrinsically disordered proteins. It is a soluble protein that is highly expressed in neurons and expressed at low levels in glial cells. The monomeric protein aggregation process induces the formation of oligomeric intermediates and proceeds towards fibrillar species. These α-syn conformational species have been detected in the extracellular space and mediate consequences on surrounding neurons and glial cells. In particular, higher-ordered α-syn aggregates are involved in microglial and oligodendrocyte activation, as well as in the induction of astrogliosis. These phenomena lead to mitochondrial dysfunction, reactive oxygen and nitrogen species formation, and the induction of an inflammatory response, associated with neuronal cell death. Several receptors participate in cell activation and/or in the uptake of α-syn, which can vary depending on the α-syn aggregated state and cell types. The receptors involved in this process are of outstanding relevance because they may constitute potential therapeutic targets for the treatment of PD and related synucleinopathies. This review article focuses on the mechanism associated with extracellular α-syn uptake in glial cells and the consequent glial cell activation that contributes to the neuronal death associated with synucleinopathies.

Keywords: astrocytes; extracellular alpha-synuclein; fibrils; microglia; oligodendrocytes; oligomers.

Figure 1

Left. Immunofluorescence for the detection of GFAP (red) and α-syn (green). Nuclei were stained with DAPI (blue). Primary culture of cortical astrocytes obtained from neonate rats was exposed for 24 h to different α-syn species. Right. Schematic representation of astrocyte and its interactions with different α-syn conformers, showing (a) endocytosis pathway of high-molecular-weight species, (b) cell membrane translocation of α-syn monomer, (c) lysosomal degradation process, and (d) cytoplasmic liberation and interaction with different cell organelles and proteins.

Figure 2

Illustration of glial cells and neurons and their interactions with different α-syn conformers, showing (a) liberation of proinflammatory cytokines from astroglial and microglial cells, contributing to their activation, (b) liberation of proinflammatory cytokines from microglial cells that affect neurons, (c) activation of astrocytes, impairing trophic support to neurons, and (d) myelination deficiency, negatively affecting axonal conduction and neuronal function.