-Synuclein pathology from the body to the brain: so many seeds so close to the central soil

alpha-Synuclein is a protein that mainly exists in the presynaptic terminals. Abnormal folding and accumulation of alpha-synuclein are found in several neurodegenerative diseases, including Parkinson's disease. Aggregated and highly phosphorylated alpha-synuclein constitutes the main component of Lewy bodies in the brain, the pathological hallmark of Parkinson's disease. For decades, much attention has been focused on the accumulation of alpha-synuclein in the brain parenchyma rather than considering Parkinson's disease as a systemic disease. Recent evidence demonstrates that, at least in some patients, the initial alpha-synuclein pathology originates in the peripheral organs and spreads to the brain. Injection of alpha-synuclein preformed fibrils into the gastrointestinal tract triggers the gut-to-brain propagation of alpha-synuclein pathology. However, whether alpha-synuclein pathology can occur spontaneously in peripheral organs independent of exogenous alpha-synuclein preformed fibrils or pathological alpha-synuclein leakage from the central nervous system remains under investigation. In this review, we aimed to summarize the role of peripheral alpha-synuclein pathology in the pathogenesis of Parkinson's disease. We also discuss the pathways by which alpha-synuclein pathology spreads from the body to the brain.