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 alpha-synuclein (alpha-syn). Here, we analyze the effect of different species of alpha-syn, including monomeric, oligomeric and fibrillar forms of the protein, on rat astrocytes. Astrocytes treated with these distinct forms of alpha-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 alpha-syn. Further exploration of the mechanisms behind astrocyte activation and cytotoxicity revealed differences between the assessed alpha-syn species. Only oligomers induced mitochondria) dysfunction in astrocytes and significantly increased extracellular hydrogen peroxide production by these cells, Besides, TNF-alpha and IL-1 beta (interleukin 1 beta) expression presented different kinetics and levels depending on which species induced the response. Our data suggest that alpha-syn species (monomeric, oligomeric and fibrillar) induce astrocyte activation that can lead to neuronal death. Nevertheless, the tested a-syn species act through different preferential mechanisms and potency. All together these results help to understand the effect of a-syn species on astrocyte function and their potential impact on the pathogenesis of Parkinson's disease and related alpha-synucleinopathies.