Alpha-synuclein and its direct effects on microglial activation
Beraud, Dawn Altia
Accumulation, deposition and dysfunction of α-synuclein occur in a class of neurodegenerative disorders known as synucleinopathies. These include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Many lines of experimental evidence highlight the relevance of glial reactivity and dysfunction in synucleinopathies. For example, α-synuclein has been directly linked to microglial activation in vitro and increased numbers of activated microglia have been reported in an α-synuclein overexpressing transgenic mouse, prior to neuronal loss. However, the mechanism by which α-synuclein incites microglial activation has not been fully described. Microglial activation is governed in part, by pattern recognition receptors (PRRs) that detect foreign material and additionally recognize changes in homeostatic cellular conditions. Upon proinflammatory pathway initiation, activated microglia contribute to oxidative stress through release of cytokines, nitric oxide, and other reactive oxygen species, which may adversely impact adjacent neurons. Here we show that misfolded α;-synuclein activates microglia, as assessed by increases in proinflammatory cytokine expression and release (TNF-α and IL-1β), nitric oxide levels, antioxidant responses and PRR gene expression. Importantly, we demonstrate that it is the fibril-containing high molecular weight oligomer of misfolded α-synuclein that drives microglial activation. Specifically, we show increased protein expression of antioxidant enzyme heme oxygenase-1 as well as increased gene expression of a number of Nrf2 regulated antioxidant genes following stimulation with misfolded α-synuclein. We also demonstrate increased expression of multiple Toll-like receptors following misfolded α-synuclein stimulation of microglia. Moreover, we show that these proinflamatory effects are attenuated following pre-treatment with a MyD88 inhibitor, demonstrating that α-synuclein-mediated microglial activation is partially MyD88 dependent.
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