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

Academic Article

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.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Challis C; Hori A; Sampson TR; Yoo BB; Challis RC; Hamilton AM; Mazmanian SK; Volpicelli-Daley LA; Gradinaru V
  • Start Page

  • 327
  • End Page

  • 336
  • Volume

  • 23
  • Issue

  • 3