The classic view portrays Parkinson disease (PD) as a motor disorder resulting from loss of substantia nigra pars compacta dopaminergic neurons. Multiple studies, however, describe prodromal, non-motor dysfunctions that affect the quality of life of patients who subsequently develop PD. These prodromal dysfunctions comprise a wide array of gastrointestinal motility disorders including dysphagia, delayed gastric emptying and chronic constipation. The histological hallmark of PD — misfolded α-synuclein aggregates that form Lewy bodies and neurites — is detected in the enteric nervous system prior to clinical diagnosis, suggesting that the gastrointestinal tract and its neural (vagal) connection to the central nervous system could have a major role in disease aetiology. This Review provides novel insights on the pathogenesis of PD, including gut-to-brain trafficking of α-synuclein as well as the newly discovered nigro–vagal pathway, and highlights how vagal connections from the gut could be the conduit by which ingested environmental pathogens enter the central nervous system and ultimately induce, or accelerate, PD progression. The pathogenic potential of various environmental neurotoxicants and the suitability and translational potential of experimental animal models of PD will be highlighted and appraised. Finally, the clinical manifestations of gastrointestinal involvement in PD and medications will be discussed briefly.
Gastrointestinal dysfunction, including dysphagia, delayed gastric emptying and constipation, can be detected up to 20 years prior to Parkinson disease (PD) diagnosis.
Lack of understanding of the mechanisms and pathophysiology hamper the diagnosis and clinical treatment of PD-related gastrointestinal dysfunction.
Both a ‘bottom-up’ and ‘top-down’ aetiology of PD have been proposed; experimental evidence suggests that these hypotheses are not mutually exclusive.
Experimental as well as clinical data suggest that PD is more a circuit-restricted than a cell-restricted disease.
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The authors thank the NIH (grants DK 55530 and DK 124098 to R.A.T., DK 111667 to K.N.B. and DK 115950 and 122280 to M.C.), the National Parkinson Foundation (R.A.T.), and the Michael J. Fox Foundation for Parkinson’s Disease (R.A.T.) for their support. The authors also thank C. M. Travagli, Z. Travagli and W. N. Browning for support and encouragement.
M.C. serves as a member of Scientific Advisory Board of Enterin, a company that is developing a medication for Parkinson Disease. The other authors declare no competing interests.
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Travagli, R.A., Browning, K.N. & Camilleri, M. Parkinson disease and the gut: new insights into pathogenesis and clinical relevance. Nat Rev Gastroenterol Hepatol 17, 673–685 (2020). https://doi.org/10.1038/s41575-020-0339-z
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