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Intestinal infection triggers mitochondria-mediated α-synuclein pathology: relevance to Parkinson’s disease

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Abstract

Parkinson’s disease (PD) is a multifactorial neurodegenerative disease characterized by the loss of dopaminergic neurons in the midbrain. In the prodromal phase several autonomic symptoms including orthostatic hypotension and constipation are correlated with increased α-synuclein pathology in peripheral tissues. It is currently accepted that some idiopathic PD cases may start in the gut (body-first PD) with accumulation of pathological α-synuclein in enteric neurons that may subsequently propagate caudo-rostrally to the central nervous system. In addition to the already-established regulation of synaptic vesicle trafficking, α-synuclein also seems to play a role in neuronal innate immunity after infection. Our goal was to understand if seeding the gut with the foodborne pathogen Listeria monocytogenes by oral gavage would impact gut immunity and eventually the central nervous system. Our results demonstrate that L. monocytogenes infection induced oligomerization of α-synuclein in the ileum, along with a pronounced pro-inflammatory local and systemic response that ultimately culminated in neuronal mitochondria dysfunction. We propose that, having evolved from ancestral endosymbiotic bacteria, mitochondria may be directly targeted by virulence factors of intracellular pathogens, and that mitochondrial dysfunction and fragmentation resulting also from the activation of the innate immune system at the gut level, trigger innate immune responses in midbrain neurons, which include α-synuclein oligomerization and neuroinflammation, all of which hallmarks of PD.

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Data availability statement

The datasets generated during and/or analyzed during the current study are not publicly available since we do not have a repository but are available from the corresponding author on reasonable request.

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Funding

This work was funded by Portuguese national funds via FCT – Fundação para a Ciência e a Tecnologia through projects PTDC/MED-NEU/3644/2020 (including a Junior Investigator contract to E. C.), PTDC/BIA-MIC/0122/2021, UIDB/04539/2020, UIDP/04539/2020 and LA/P/0058/2020. J.D.M. is supported by PD/BD/146409/2019 PhD fellowship.

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Authors and Affiliations

  1. CNC–Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    João D. Magalhães, Emanuel Candeias, Inês Melo-Marques, Diana F. Silva, A. Raquel Esteves, Nuno Empadinhas & Sandra Morais Cardoso

  2. CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal

    João D. Magalhães, Emanuel Candeias, Inês Melo-Marques, Diana F. Silva, A. Raquel Esteves, Nuno Empadinhas & Sandra Morais Cardoso

  3. Ph.D. Programme in Biomedicine and Experimental Biology (PDBEB), Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal

    João D. Magalhães

  4. Faculty of Medicine, Institute of Cellular and Molecular Biology, University of Coimbra, Coimbra, Portugal

    Sandra Morais Cardoso

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  1. João D. Magalhães
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SMC and NE conceived and designed this study. Material preparation, data collection and analysis were performed by JDM, EC, IM-M, DFS and SMC. A draft version of the manuscript was prepared by JDM. NE and SMC revised the final version of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Nuno Empadinhas or Sandra Morais Cardoso.

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18_2023_4819_MOESM1_ESM.tif

Supplementary file1 Supplemental Figure 1. Neurons secrete inflammatory cytokines in response to Lm4b infection. (A) IL-1β and (B) IL-6 levels were measured in neuronal conditioned media with ELISA kits (B, Unt vs Lm4b, *p<0.05). (C) Representative image of Western Blot against aSyn in untreated (Unt) and infected (Lm4b) cells. (D) aSyn relative abundance (Unt vs Lm4b, **p<0.01). Data represents mean + SEM. Unpaired Student’s t-test was performed in A, C, D. (TIF 2157 KB)

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D. Magalhães, J., Candeias, E., Melo-Marques, I. et al. Intestinal infection triggers mitochondria-mediated α-synuclein pathology: relevance to Parkinson’s disease. Cell. Mol. Life Sci. 80, 166 (2023). https://doi.org/10.1007/s00018-023-04819-3

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