Astrocyte alterations in α-synucleinopathies

Abstract

Despite long being considered to be passive and supportive cells, in the last decades astrocytes have arisen as key regulators of neuronal excitability, synaptic transmission and plasticity. Since the discovery of the tripartite synapse, accumulating evidence suggests that astrocytes are involved in the pathogenesis of neurodegenerative diseases, including α-synucleinopathies. Here we will discuss recent evidence showing that astrocytes express endogenous α-synuclein and the implications of this protein in astrocyte cellular processes. Furthermore, we review how the expression of pathological forms of this protein in astrocytes leads to aberrant cytosolic Ca²⁺ activity in these cells and to alterations in gliotransmission and pathology progression.

Keywords: astrocytes; gliotransmission; tripartite synapse; α-synuclein; α-synucleinopathies.

FIGURE 1

(A) Schematic drawing of the α-synuclein protein indicating its three domains: N-terminal domain (green), amyloid-binding central domain (NAC, blue) and C-terminal domain (orange). The position of the mutations and modifications mentioned in this review have been included. (B) Different structural conformations of α-synuclein that can be found in non-pathological and pathological conditions. (C) Progression in the formation of the different α-synuclein aggregates found in pathology.

FIGURE 2

α-synuclein transfer, degradation, expression and regulation between astrocytes and other cells. (A) α-synuclein (α-syn) transfer. It has been established that the process of transfer occurs between neurons and astrocytes via the uptake of aggregates of α-syn from the extracellular medium through endosomes. This transfer is bidirectional, yet it is less efficient in the astrocyte-to-neuron direction. Furthermore, direct transfer from the medium also appears to be possible, as well as a recently discovered mechanism whereby transfer between astrocytes can occur through tunneling nanotubes. (B) Endogenous expression: The expression of α-syn protein has been observed in cultured mouse astrocytes and in a human astrocyte cell line. The expression of both α-syn mRNA and protein has been observed to increase upon exposure to interleukin 1β (IL-1β) in culture. In addition, it has been demonstrated that astrocytes are capable of degrading α-syn aggregates, a capacity that is augmented following IL-1β exposure. (C) Regulation: Recent studies suggest that the surrounding cellular environment may also influence this ability to degrade α-syn aggregates. When astrocyte cultures are co-cultured with microglia, the degradation of α-syn aggregates increases, likely due to the release of interleukins such as IL-1β.

FIGURE 3

α-synuclein and their potential role in the regulation of cytosolic Ca²⁺. α-synuclein (α-syn) oligomers and overexpression of α-syn induce Ca²⁺ dependent glutamate release in astrocytes, leading to extrasynaptic N-methyl-D-aspartate (NMDA) receptors activation in neurons. This triggers the activation of pro-apoptotic signaling pathways, ultimately resulting in synaptic loss and neuronal death. Furthermore, the activation of these receptors mediates slow inward currents (SICs) in neurons, which can be used to assay astrocyte-derived glutamate release.