Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice

Parkinson’s disease (PD) is a synucleinopathy that is characterized by motor dysfunction, death of midbrain dopaminergic neurons, and accumulation of alpha synuclein (α-Syn) aggregates. Evidence suggests that α-Syn aggregation can originate in peripheral tissues and progress to the brain via autonomic fibers. We tested this by inoculating the duodenal wall of mice with α-Syn preformed fibrils. Following inoculation, we observed gastrointestinal deficits and physiological changes to the enteric nervous system. We also found that α-Syn pathology is reduced by increased expression of the lysosomal enzyme glucocerebrosidase, using the AAV-PHP.S capsid to target this protein for peripheral gene transfer. Lastly, inoculation of α-Syn fibrils in aged mice, but not younger mice, resulted in progression of α-Syn histopathology to the midbrain and subsequent motor defects. Our results characterize peripheral synucleinopathy in prodromal PD and explore cellular mechanisms for the gut-to-brain progression of α-Syn pathology.