Food and Behaviour Research

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

Challis C, Hori A, Sampson TR, Yoo BB, Challis RC, Hamilton AM, Mazmanian SK, Volpicelli-Daley LA, Gradinaru V (2020) Nat Neurosci.  2020 Feb.  doi: 10.1038/s41593-020-0589-7. [Epub ahead of print] 

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Abstract:

Parkinson's disease is a synucleinopathy that is characterized by motor dysfunction, death of midbrain dopaminergic neurons and accumulation of α-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. Using the AAV-PHP.S capsid to target the lysosomal enzyme glucocerebrosidase for peripheral gene transfer, we found that α-Syn pathology is reduced due to the increased expression of this protein. 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 Parkinson's disease and explore cellular mechanisms for the gut-to-brain progression of α-Syn pathology.