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Interaction of an α-synuclein epitope with HLA-DRB1*15:01 initiates early enteric features of Parkinson’s disease in humanized mice

View ORCID ProfileFrancesca Garretti, View ORCID ProfileConnor Monahan, Nicholas Sloan, Sanjid Shariar, Seon Woo Kim, View ORCID ProfileAlessandro Sette, Tyler Cutforth, View ORCID ProfileEllen Kanter, View ORCID ProfileDritan Agalliu, View ORCID ProfileDavid Sulzer
doi: https://doi.org/10.1101/2022.02.03.479014
Francesca Garretti
1Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
2Departments of Psychiatry and Pharmacology, Columbia University Irving Medical Center, New York, NY, USA
9Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815
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  • ORCID record for Francesca Garretti
Connor Monahan
2Departments of Psychiatry and Pharmacology, Columbia University Irving Medical Center, New York, NY, USA
9Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815
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Nicholas Sloan
3Department of Neuroscience, Columbia University Irving Medical Center, New York, NY, USA
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Sanjid Shariar
1Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
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Seon Woo Kim
4Weill Cornell Medicine—Qatar, Education City, Doha, Qatar
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Alessandro Sette
4Weill Cornell Medicine—Qatar, Education City, Doha, Qatar
5Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, USA
9Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815
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Tyler Cutforth
7Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
9Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815
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Ellen Kanter
2Departments of Psychiatry and Pharmacology, Columbia University Irving Medical Center, New York, NY, USA
8Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
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Dritan Agalliu
1Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
7Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
9Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815
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  • For correspondence: ds43@cumc.columbia.edu da191@cumc.columbia.edu
David Sulzer
2Departments of Psychiatry and Pharmacology, Columbia University Irving Medical Center, New York, NY, USA
7Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
8Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
9Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815
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  • For correspondence: ds43@cumc.columbia.edu da191@cumc.columbia.edu
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SUMMARY

Parkinson’s disease (PD) patients possess circulating T cells that recognize specific α-synuclein-(α-syn)-derived epitopes. One epitope, α-syn32-46, interacts strongly with the HLA-DRB1*15:01 allele implicated in multiple autoimmune diseases. Whether this interaction and α-syn-specific T cells play roles in PD pathogenesis remains unknown. We report that α-syn32-46 immunization of a humanized mouse that expresses HLA-DRB1*15:01 triggers intestinal inflammation. This enteric pathology is characterized by activation of innate and adaptive immune responses and type I interferon signaling as well as loss of enteric dopaminergic neurons in the submucosal plexus, and results in constipation and weight loss. Depletion of CD4+, but not CD8+, T cells partially rescues enteric neurodegeneration. Thus, an interaction between α-syn32-46 and HLA-DRB1*15:01 induces gut inflammation and CD4+ T cell-mediated loss of enteric dopaminergic neurons in the humanized mice. These findings suggest a mechanism for the prodromal enteric features of PD and indicate future directions for disease screening and treatment.

HIGHLIGHTS AND eTOC Blurb

  1. α-syn32-46 immunization of a HLA-DRB1*15:01 mouse triggers weight loss and constipation.

  2. α-syn32-46 immunizations induce gut inflammation and loss of enteric dopaminergic neurons.

  3. Depletion of CD4+, but not CD8+, T cells partially rescues enteric neurodegeneration.

  4. Interaction between α-syn32-46 and HLA-DRB1*15:01 are critical for the prodromal phase of PD.

HIGHLIGHTS AND eTOC BlurbParkinson’s disease (PD) patients have circulating T cells that recognize α-synuclein-(α-syn)-epitopes. One epitope α-syn32-46, interacts with the HLA-DRB1*15:01; however, its role in PD pathogenesis remains unknown. Garretti et al. show that α-syn32-46 immunization of a humanized mouse expressing HLA-DRB1*15:01 triggers intestinal inflammation, loss of enteric dopaminergic neurons, constipation and weight loss, suggesting a critical role in the prodromal PD.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 05, 2022.
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Interaction of an α-synuclein epitope with HLA-DRB1*15:01 initiates early enteric features of Parkinson’s disease in humanized mice
Francesca Garretti, Connor Monahan, Nicholas Sloan, Sanjid Shariar, Seon Woo Kim, Alessandro Sette, Tyler Cutforth, Ellen Kanter, Dritan Agalliu, David Sulzer
bioRxiv 2022.02.03.479014; doi: https://doi.org/10.1101/2022.02.03.479014
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Interaction of an α-synuclein epitope with HLA-DRB1*15:01 initiates early enteric features of Parkinson’s disease in humanized mice
Francesca Garretti, Connor Monahan, Nicholas Sloan, Sanjid Shariar, Seon Woo Kim, Alessandro Sette, Tyler Cutforth, Ellen Kanter, Dritan Agalliu, David Sulzer
bioRxiv 2022.02.03.479014; doi: https://doi.org/10.1101/2022.02.03.479014

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