Extracellular α-synuclein-a novel and crucial factor in Lewy body diseases

Misfolding and intracellular aggregation of alpha-synuclein are thought to be crucial factors in the pathogenesis of Lewy body diseases (LBDs), such as Parkinson disease. However, the pathogenic modifications of this protein and the mechanisms underlying its activity have not been fully characterized. Recent studies suggest that small amounts of alpha-synuclein are released from neuronal cells by unconventional exocytosis, and that this extracellular alpha-synuclein contributes to the major pathological features of LBD, such as neurodegeneration, progressive spreading of alpha-synuclein pathology, and neuroinflammation. In this article, we review a rapidly growing body of literature on possible mechanisms by which extracellular alpha-synuclein contributes to LBD pathology, and discuss therapeutic approaches to target this form of alpha-synuclein to halt disease progression.