Parkinson's Disease and the Gut: Models of an Emerging Relationship.

Abstract Parkinson's disease (PD) is a common neurodegenerative disease characterized by a progressive loss of fine motor function that impacts 1-2 out of 1,000 people. PD occurs predominately late in life and lacks a definitive biomarker for early detection. Recent cross-disciplinary progress has implicated the gut as a potential origin of PD pathogenesis. The gut-origin hypothesis has motivated research on gut PD pathology and transmission to the brain, especially during the prodromal stage (10-20 years before motor symptom onset). Early findings have revealed several possible triggers for Lewy pathology – the pathological hallmark of PD – in the gut, suggesting that microbiome and epithelial interactions may play a greater than appreciated role. But the mechanisms driving Lewy pathology and gut-brain transmission in PD remain unknown. Development of artificial α-Synuclein aggregates (α-Syn preformed fibrils) and animal disease models have recapitulated features of PD progression, enabling for the first time, controlled investigation of the gut-origin hypothesis. However, the role of specific cells in PD transmission, such as neurons, remains limited and requires in vitro models for controlled evaluation and perturbation. Human cell populations, three-dimensional organoids, and microfluidics as discovery platforms inch us closer to improving existing treatment for patients by providing platforms for discovery and screening. This review includes a discussion of PD pathology, conventional treatments, in vivo and in vitro models, and future directions.