Extracellular Interactions of Alpha-Synuclein in Multiple System Atrophy

Multiple system atrophy, characterized by atypical Parkinsonism, results from central nervous system (CNS) cell loss and dysfunction linked to aggregates of the normally pre-synaptic -synuclein protein. Mostly cytoplasmic pathological -synuclein inclusion bodies occur predominantly in oligodendrocytes in affected brain regions and there is evidence that -synuclein released by neurons is taken up preferentially by oligodendrocytes. However, extracellular -synuclein has also been shown to interact with other neural cell types, including astrocytes and microglia, as well as extracellular factors, mediating neuroinflammation, cell-to-cell spread and other aspects of pathogenesis. Here, we review the current evidence for how -synuclein present in the extracellular milieu may act at the cell surface to drive components of disease progression. A more detailed understanding of the important extracellular interactions of -synuclein with neuronal and non-neuronal cell types both in the brain and periphery may provide new therapeutic targets to modulate the disease process.