The responses of astrocytes stimulated by extracellular a-synuclein

Abnormal neuronal aggregation of a-synuclein is implicated in the development of Parkinson’s disease. Glial cells also show extensive a-synuclein pathology and are thought to contribute to disease progression. However, the mechanism that produces the glial a-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that in neuronal cells misfolded a-synuclein proteins are selectively translocated into vesicles, leading to exocytosis of the aggregated forms. More importantly, our data demonstrate that astrocytes take up the neuron-derived a-synuclein aggregates and produce a-synuclein inclusions similar to the ones found in human brains. This uptake is paralleled by changes in the gene expression profile reflecting an inflammatory response. These results suggest that astroglial a-synuclein pathology is produced by cell-to-cell transmission of neuronal a-synuclein aggregates. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target. To determine how astrocytes respond to extracellular a-synuclein, gene expression profiles were established and analyzed for nearly 22,000 rat genes using the Illumina RatRef-12 Expression BeadChip. Total RNA was isolated from astrocytes exposed for 6h or 24h to conditioned medium from cultures of a-synuclein or lacZ expressing cells.