Interaction of an α-synuclein epitope with HLA-DRB1∗15:01 triggers enteric features in mice reminiscent of prodromal Parkinson's disease

Francesca Garretti; Connor Monahan; Nicholas Sloan; Jamie Bergen; Sanjid Shahriar; Seon Woo Kim; Alessandro Sette; Tyler Cutforth; Ellen Kanter; Dritan Agalliu; David Sulzer

doi:10.1016/j.neuron.2023.07.015

Interaction of an α-synuclein epitope with HLA-DRB1^∗15:01 triggers enteric features in mice reminiscent of prodromal Parkinson's disease

Neuron. 2023 Nov 1;111(21):3397-3413.e5. doi: 10.1016/j.neuron.2023.07.015. Epub 2023 Aug 18.

Authors

Affiliations

¹ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA; Departments of Psychiatry and Pharmacology, Columbia University Irving Medical Center, New York, NY, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
² Departments of Psychiatry and Pharmacology, Columbia University Irving Medical Center, New York, NY, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
³ Department of Neuroscience, Columbia University, New York, NY, USA.
⁴ Department of Neuroscience, Columbia University, New York, NY, USA; Department of Computer Science, Columbia University, New York, NY, USA.
⁵ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
⁶ Weill Cornell Medicine - Qatar, Education City, Doha, Qatar.
⁷ Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, USA; Department of Medicine, University of California in San Diego, San Diego, CA, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
⁸ Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
⁹ Departments of Psychiatry and Pharmacology, Columbia University Irving Medical Center, New York, NY, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
¹⁰ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. Electronic address: [email protected].
¹¹ Departments of Psychiatry and Pharmacology, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. Electronic address: [email protected].

Abstract

Enteric symptoms are hallmarks of prodromal Parkinson's disease (PD) that appear decades before the onset of motor symptoms and diagnosis. PD patients possess circulating T cells that recognize specific α-synuclein (α-syn)-derived epitopes. One epitope, α-syn_32-46, binds with strong affinity to the HLA-DRB1^∗15:01 allele implicated in autoimmune diseases. We report that α-syn_32-46 immunization in a mouse expressing human HLA-DRB1^∗15:01 triggers intestinal inflammation, leading to loss of enteric neurons, damaged enteric dopaminergic neurons, constipation, and weight loss. α-Syn_32-46 immunization activates innate and adaptive immune gene signatures in the gut and induces changes in the CD4⁺ T_H1/T_H17 transcriptome that resemble tissue-resident memory (T_RM) cells found in mucosal barriers during inflammation. Depletion of CD4⁺, but not CD8⁺, T cells partially rescues enteric neurodegeneration. Therefore, interaction of α-syn_32-46 and HLA-DRB1^∗15:0 is critical for gut inflammation and CD4⁺ T cell-mediated loss of enteric neurons in humanized mice, suggesting mechanisms that may underlie prodromal enteric PD.

Keywords: CD4(+) T cells; HLA-DRB1(∗)15:01; Parkinson’s disease; antigen-experienced T(RM); constipation; enteric dopaminergic neurons; mucosal barriers; neo-antigen; prodromal disease; α-synuclein.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dopaminergic Neurons / metabolism
Epitopes
HLA-DRB1 Chains / genetics
Humans
Inflammation
Mice
Parkinson Disease* / genetics
Parkinson Disease* / metabolism
alpha-Synuclein / genetics
alpha-Synuclein / metabolism

Substances

alpha-Synuclein
HLA-DRB1 Chains
Epitopes

Abstract

Publication types

MeSH terms

Substances

Grants and funding