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Published March 2020 | Accepted Version + Supplemental Material
Journal Article Open

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

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.

Additional Information

© 2020 Springer Nature Limited. Received 12 February 2019; Accepted 09 January 2020; Published 17 February 2020. We thank C. Bedbrook for help with calcium imaging and K. Beadle and E. Mackey for additional technical support. This work was supported by the following grants to V.G.: NIH Director's New Innovator IDP20D017782-01 and PECASE; NIH/NIA R01AG047664-01; NIH BRAIN 1U01NS090577; the Heritage Medical Research Institute; the Pew Charitable Trust; the Rogers Fellowship for Parkinson's Research and the CZI Neurodegeneration Challenge Network. C.C. was supported by NIH/NIA F32AG054101. S.K.M. was supported by NIH/NINDS R01NS085910. V.G. and S.K.M. were supported by Department of Defense grant W81XWH-17-1-0588. L.A.V.-D. was supported by NINDS R01NS102257 and Morris K. Udall Centers of Excellence for Parkinson's Disease Research P50NS108675. T.R.S was supported by the Larry L. Hillblom Foundation. B.B.Y. was supported by NIH/NIGMS 5T32GM007616 and the Caltech Center for Environmental Microbial Interactions (CEMI). Data availability: No datasets were generated or analyzed during the current study. The data that support the findings of this study are available from the corresponding author upon request. Author Contributions: C.C. and V.G. conceptualized the study and developed the research plan. C.C., V.G. and L.A.V.-D. designed the study. L.A.V.-D. generated the α-Syn PFFs and α-Syn monomers. C.C. performed the animal surgeries, tissue clearing, histology, calcium imaging and retro-orbital viral injections. C.C., A.H. and T.R.S. performed the behavior experiments. C.C., B.B.Y. and R.C.C. performed virus production, purification and verification. C.C. and T.R.S. performed protein analyses. C.C., B.B.Y. and R.C.C. performed confocal imaging. A.M.H. and T.R.S. performed RNA extraction and quantitative PCR analyses. C.C. performed data analyses. S.K.M. provided key reagents and methods. C.C. and V.G. wrote the manuscript. All authors contributed to discussion. V.G. supervised all the work. The authors declare no competing interests.

Attached Files

Accepted Version - nihms-1548772.pdf

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Additional details

Created:
August 22, 2023
Modified:
December 22, 2023