Journal
NATURE NEUROSCIENCE
Volume 23, Issue 3, Pages 327-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41593-020-0589-7
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Funding
- NIH [IDP20D017782-01]
- PECASE
- NIH/NIA [R01AG047664-01, F32AG054101]
- NIH BRAIN [1U01NS090577]
- Heritage Medical Research Institute
- Pew Charitable Trust
- Rogers Fellowship for Parkinson's Research
- CZI Neurodegeneration Challenge Network
- NIH/NINDS [R01NS085910]
- Department of Defense grant [W81XWH-17-1-0588]
- NINDS [R01NS102257]
- Morris K. Udall Centers of Excellence for Parkinson's Disease Research [P50NS108675]
- Larry L. Hillblom Foundation
- NIH/NIGMS [5T32GM007616]
- Caltech Center for Environmental Microbial Interactions (CEMI)
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Parkinson's disease is a synucleinopathy that is characterized by motor dysfunction, death of midbrain dopaminergic neurons and accumulation of alpha-synuclein (alpha-Syn) aggregates. Evidence suggests that alpha-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 alpha-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 alpha-Syn pathology is reduced due to the increased expression of this protein. Lastly, inoculation of alpha-Syn fibrils in aged mice, but not younger mice, resulted in progression of alpha-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 alpha-Syn pathology. Alpha-synuclein fibrils can disrupt the enteric nervous system, which is mitigated by peripheral GBA1 gene transfer via systemic AAVs. Aging increases susceptibility to alpha-synuclein pathology progression from the gut to the brain.
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