Dataset Information

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

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.

SUBMITTER: McFleder RL

PROVIDER: S-EPMC10658151 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Brain-to-gut trafficking of alpha-synuclein by CD11c<sup>+</sup> cells in a mouse model of Parkinson's disease.

McFleder Rhonda L RL Makhotkina Anastasiia A Groh Janos J Keber Ursula U Imdahl Fabian F Peña Mosca Josefina J Peteranderl Alina A Wu Jingjing J Tabuchi Sawako S Hoffmann Jan J Karl Ann-Kathrin AK Pagenstecher Axel A Vogel Jörg J Beilhack Andreas A Koprich James B JB Brotchie Jonathan M JM Saliba Antoine-Emmanuel AE Volkmann Jens J Ip Chi Wang CW

Nature communications 20231120 1

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 th ...[more]

PMID: 37981650

Similar Datasets

Project description:Decreased clearance of α-synuclein (aSyn) and aSyn protein misfolding and aggregation are seen as major factors in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies that leads to disruption in neuronal function and eventually to cell death. Prolyl oligopeptidase (PREP) can accelerate the aSyn aggregation process, while inhibition of PREP by a small molecule inhibitor decreases aSyn oligomer formation and enhances its clearance via autophagy in different aSyn overexpressing cell types and in transgenic PD animal models. In this study, we investigated the impact of chronic PREP inhibition by a small molecule inhibitor, 4-phenylbutanoyl-l-prolyl-2(S)-cyanopyrrolidine (KYP-2047), on aSyn oligomerization, clearance, and underlying spontaneous motor behavior in a virus vector-based aSyn overexpression mouse model 4 weeks after aSyn microinjections and after the onset of symptomatic forepaw bias. Following 4 weeks of PREP inhibition, we saw an improved spontaneous forelimb use in mice that correlated with a decreased immunoreactivity against oligomer-specific forms of aSyn. Additionally, KYP-2047 had a trend to enhance dopaminergic systems activity. Our results suggest that PREP inhibition exhibits a beneficial effect on the aSyn clearance and aggregation in a virus mediated aSyn overexpression PD mouse model and that PREP inhibitors could be a novel therapeutic strategy for synucleinopathies.Significance statementAlpha-synuclein (aSyn) has been implicated in Parkinson's disease, with aSyn aggregates believed to exert toxic effects on neurons, while prolyl oligopeptidase (PREP) has been shown to interact with aSyn both in cells and cell free conditions, thus enhancing its aggregation. We demonstrate the possibility to abolish motor imbalance caused by aSyn viral vector injection with chronic 4 week PREP inhibition by a potent small-molecule PREP inhibitor, 4-phenylbutanoyl-l-prolyl-2(S)-cyanopyrrolidine (KYP-2047). Treatment was initiated postsymptomatically, 4 weeks after aSyn injection. KYP-2047-treated animals had a significantly decreased amount of oligomeric aSyn particles and improved dopamine system activity compared to control animals. To our knowledge, this is the first time viral overexpression of aSyn has been countered and movement impairments abolished after their onset.

Dataset Information

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

Publications

Brain-to-gut trafficking of alpha-synuclein by CD11c<sup>+</sup> cells in a mouse model of Parkinson's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Publications

Brain-to-gut trafficking of alpha-synuclein by CD11c&lt;sup&gt;+&lt;/sup&gt; cells in a mouse model of Parkinson's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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

Brain-to-gut trafficking of alpha-synuclein by CD11c<sup>+</sup> cells in a mouse model of Parkinson's disease.