Impact of monomeric, oligomeric and fibrillar alpha-synuclein on astrocyte reactivity and toxicity to neurons

Synucleinopathies are a group of neurodegenerative disorders characterized by the presence of aggregated and fibrillar forms of α-synuclein (α-syn). Herein we analyse the effect of different species of α-syn including monomeric, oligomeric, and fibrillar forms of the protein, on rat astrocytes. Astrocytes treated with these distinct forms of α-syn showed an increase in long and thin processes and glial fibrillary acidic protein expression, indicating cell activation; high levels of intracellular oxidants and increased expression of cytokines. Moreover, astrocytes incubated with the different species induced hippocampal neuronal death in co-culture, and cytotoxicity was particularly enhanced by exposure to fibrillar α-syn. Further exploration of the mechanisms behind astrocyte activation and cytotoxicity revealed differences between the assessed α-syn species. Only oligomers induced mitochondrial dysfunction in astrocytes and significantly increased extracellular hydrogen peroxide production by these cells. Besides, TNF-alpha and IL-1β expression presented different kinetics and levels depending on which species induced the response. Our data suggest that α-syn species (monomeric, oligomeric and fibrillar) induce astrocyte activation that can lead to neuronal death. Nevertheless, the tested α-syn species act through different preferential mechanisms and potency. All together these results help to understand the effect of α-syn species on astrocyte function and their potential impact on the pathogenesis of Parkinson9s disease and related α-synucleinopathies.