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

Challis, Collin and Hori, Acacia and Sampson, Timothy R. and Yoo, Bryan B. and Challis, Rosemary C. and Hamilton, Adam M. and Mazmanian, Sarkis K. and Volpicelli-Daley, Laura A. and Gradinaru, Viviana (2020) Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice. Nature Neuroscience, 23 (3). pp. 327-336. ISSN 1097-6256. PMCID PMC7065967 . https://resolver.caltech.edu/CaltechAUTHORS:20191209-154036633

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41593-020-0589-7DOIArticle
https://rdcu.be/b1RsKPublisherFree ReadCube access
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7065967/PubMed CentralArticle
ORCID:
AuthorORCID
Challis, Collin0000-0003-4716-6086
Hori, Acacia0000-0001-5868-348X
Sampson, Timothy R.0000-0002-2486-8766
Challis, Rosemary C.0000-0003-3086-6553
Hamilton, Adam M.0000-0002-8857-3617
Mazmanian, Sarkis K.0000-0003-2713-1513
Volpicelli-Daley, Laura A.0000-0001-8934-4018
Gradinaru, Viviana0000-0001-5868-348X
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.
Group:Heritage Medical Research Institute, Caltech Center for Environmental Microbial Interactions (CEMI), Tianqiao and Chrissy Chen Institute for Neuroscience
Funders:
Funding AgencyGrant Number
NIHIDP20D017782-01
NSFUNSPECIFIED
NIHR01AG047664-01
NIH1U01NS090577
Heritage Medical Research InstituteUNSPECIFIED
Pew Charitable TrustUNSPECIFIED
Rogers Fellowship for Parkinson’s ResearchUNSPECIFIED
CZI Neurodegeneration Challenge NetworkUNSPECIFIED
NIH Postdoctoral FellowshipF32AG054101
NIHR01NS085910
Department of DefenseW81XWH-17-1-0588
NIHR01NS102257
NIHP50NS108675
Larry L. Hillblom FoundationUNSPECIFIED
NIH Postdoctoral Fellowship5T32GM007616
Caltech Center for Environmental Microbial Interactions (CEMI)UNSPECIFIED
Subject Keywords:Ageing; Enteric nervous system; Genetic transduction; Neural circuits; Neurodegeneration
Issue or Number:3
PubMed Central ID:PMC7065967
Record Number:CaltechAUTHORS:20191209-154036633
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191209-154036633
Official Citation:Challis, C., Hori, A., Sampson, T.R. et al. Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice. Nat Neurosci 23, 327–336 (2020). https://doi.org/10.1038/s41593-020-0589-7
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100253
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:18 Feb 2020 17:18
Last Modified:02 Apr 2020 17:04

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