Brain-to-gut trafficking of alpha-synuclein by CD11c+ cells in a mouse model of Parkinson’s disease

Rhonda L. McFleder, Anastasiia Makhotkina, Janos Groh, Ursula Keber, Fabian Imdahl, Josefina Peña Mosca, Alina Peteranderl, Jingjing Wu, Sawako Tabuchi, Jan Hoffmann, Ann-Kathrin Karl, Axel Pagenstecher, Jörg Vogel, Andreas Beilhack, James B. Koprich, Jonathan M. Brotchie, Antoine-Emmanuel Saliba, Jens Volkmann and Chi Wang Ip ()
Additional contact information
Rhonda L. McFleder: University Hospital of Würzburg
Anastasiia Makhotkina: University Hospital of Würzburg
Janos Groh: Technical University Munich
Ursula Keber: Philipps University of Marburg
Fabian Imdahl: Helmholtz-Center for Infection Research (HZI)
Josefina Peña Mosca: Würzburg University Hospital
Alina Peteranderl: University Hospital of Würzburg
Jingjing Wu: University Hospital of Würzburg
Sawako Tabuchi: University Hospital of Würzburg
Jan Hoffmann: University Hospital of Würzburg
Ann-Kathrin Karl: University Hospital of Würzburg
Axel Pagenstecher: Philipps University of Marburg
Jörg Vogel: Helmholtz-Center for Infection Research (HZI)
Andreas Beilhack: Würzburg University Hospital
James B. Koprich: Atuka Inc.
Jonathan M. Brotchie: Atuka Inc.
Antoine-Emmanuel Saliba: Helmholtz-Center for Infection Research (HZI)
Jens Volkmann: University Hospital of Würzburg
Chi Wang Ip: University Hospital of Würzburg

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson’s disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, α-synuclein (αSyn). Understanding the mechanism of propagation of αSyn aggregates is essential to developing disease-modifying therapeutics. Using a brain-first mouse model of PD, we demonstrate αSyn trafficking from the brain to the ileum of male mice. Immunohistochemistry revealed that the ileal αSyn aggregations are contained within CD11c+ cells. Using single-cell RNA sequencing, we demonstrate that ileal CD11c+ cells are microglia-like and the same subtype of cells is activated in the brain and ileum of PD mice. Moreover, by utilizing mice expressing the photo-convertible protein, Dendra2, we show that CD11c+ cells traffic from the brain to the ileum. Together these data provide a mechanism of αSyn trafficking between the brain and gut.

Date: 2023
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DOI: 10.1038/s41467-023-43224-z

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