Nevertheless, most studies point to a role for α-synuclein as an exogenous stimulator of astrocytes. In postmortem PD brains, α-synuclein-positive inclusions have been found in astrocytes as well as in neurons [32, 33, 34], raising the suggestion that α-synuclein secreted by neurons is taken up by astrocytes. Multiple studies have now revealed that astrocytes can take up α-synuclein [35, 36, 37, 38], and this has been shown to occur via a TLR4-independent endocytosis pathway [37, 38]. Endocytosed α-synuclein has been shown to localise to the lysosome , suggesting that astrocytes have a role in its removal and degradation, potentially maintaining a healthy environment in which neurons can thrive.
It is also possible that astrocytes endocytose increasing levels of extracellular α-synuclein when the latter is at a high concentration, leading to the accumulation and formation of α-synuclein inclusions in astrocytes, as seen in PD brains.
This accumulation could then lead to the dysregulation of other astrocyte functions, such as glutamate uptake and blood–brain barrier integrity.
Figure 3Dysfunctional Astrocytes Contribute to Neuronal Toxicity. Astrocyte dysfunction elicits neuronal toxicity via five main mechanisms. (A) Aquaporin-4 (AQP4) water channels are mislocalised away from the astrocyte end-feet, resulting in impaired water transport. (B) The neuroprotective capacity of astrocytes is reduced because of decreased neurotrophic factor release. (C) Inflammatory signalling via the TLR4, IFN-γ, and NLPR3 inflammasome pathways is increased. (D) Astrocyte proliferation is impaired, reducing the capacity of the cells to respond to an insult. (E) Glutamate uptake is reduced, potentially resulting in increased extracellular glutamate and, therefore, neuronal excitotoxicity. Abbreviation: α-SYN, α- synuclein.
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