Potential Transmission of Alpha-Synuclein from the Gastrointestinal Tract to the Substantia Nigra along the Vagal Afferent Pathway

Parkinson's disease (PD) is characterised by dopaminergic (DA) neuron loss and the formation of Lewy bodies composed of aggregated α-synuclein (α-Syn) in the substantia nigra (SN). Emerging evidence suggests that PD may originate in the gastrointestinal (GI) tract, where α-Syn aggregates in enteroendocrine cells that synapse with vagal afferents, facilitating disease spread to the central nervous system. Using electrophysiological, behavioural, molecular, and immunohistochemical methods, we examined the effects of capsaicin-induced degeneration of vagal afferents on PD progression in models: one was prepared by injecting α-Syn preformed fibrils into the GI tract, and the other was prepared by orally administering rotenone. The results showed that vagal afferents mediate GI sensory signals affecting DA and GABA neurons in the SN. Vagal afferent degeneration reduces α-Syn accumulation in the dorsal motor nucleus of the vagus and SN while improving motor impairments, highlighting their role in α-Syn transmission and PD pathogenesis.