Gut-Induced Synuclein Propagation: A New Mechanism in Neurodegenerative Disease

Gut-induced synuclein propagation has emerged as a potential mechanism linking gastrointestinal disturbances with the development and progression of Parkinson disease and related synucleinopathies. These disorders are characterized by progressive accumulation and spreading of misfolded α-synuclein (α-Syn), leading to selective neuronal dysfunction and degeneration. Although traditionally considered brain-centered diseases, increasing evidence indicates that gastrointestinal abnormalities, peripheral α-Syn pathology, and gut-associated immune alterations may precede neurological manifestations, suggesting that peripheral processes can influence disease evolution. Here, we review clinical, pathological, and experimental evidence supporting the role of intestinal environmental stress, microbial dysregulation, barrier dysfunction, and immune activation in promoting α-Syn misfolding, aggregation, and transmission through interconnected pathways. However, peripheral α-Syn abnormalities alone are unlikely to be sufficient to initiate neurodegeneration, indicating the presence of additional biological constraints. We propose a cumulative-threshold and biological-gates framework in which α-Syn induction, seed formation, propagation efficiency, anatomical connectivity, and neuronal vulnerability collectively determine whether gut-associated pathology progresses into a self-sustaining neurodegenerative cascade. Understanding the determinants that enable gut-induced synuclein propagation may provide new insights into disease heterogeneity and guide biomarker development and mechanism-based therapeutic strategies for synucleinopathies.