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Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1−/− mice

Author

Listed:
  • Diana Matheoud

    (Université de Montréal
    Université de Montréal)

  • Tyler Cannon

    (McGill University)

  • Aurore Voisin

    (Université de Montréal)

  • Anna-Maija Penttinen

    (Université de Montréal)

  • Lauriane Ramet

    (Université de Montréal)

  • Ahmed M. Fahmy

    (Université de Montréal)

  • Charles Ducrot

    (Université de Montréal)

  • Annie Laplante

    (Université de Montréal)

  • Marie-Josée Bourque

    (Université de Montréal)

  • Lei Zhu

    (McGill University)

  • Romain Cayrol

    (Université de Montréal)

  • Armelle Campion

    (Université de Montréal)

  • Heidi M. McBride

    (McGill University)

  • Samantha Gruenheid

    (McGill University)

  • Louis-Eric Trudeau

    (Université de Montréal)

  • Michel Desjardins

    (Université de Montréal)

Abstract

Parkinson’s disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles1,2. An early-onset form of Parkinson’s disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes3. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo5–8. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens9, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson’s disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1−/− mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with l-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson’s disease, which highlights the relevance of the gut–brain axis in the disease10.

Suggested Citation

  • Diana Matheoud & Tyler Cannon & Aurore Voisin & Anna-Maija Penttinen & Lauriane Ramet & Ahmed M. Fahmy & Charles Ducrot & Annie Laplante & Marie-Josée Bourque & Lei Zhu & Romain Cayrol & Armelle Campi, 2019. "Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1−/− mice," Nature, Nature, vol. 571(7766), pages 565-569, July.
  • Handle: RePEc:nat:nature:v:571:y:2019:i:7766:d:10.1038_s41586-019-1405-y
    DOI: 10.1038/s41586-019-1405-y
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    Cited by:

    1. Véronique Sauvé & Eric Stefan & Nathalie Croteau & Thomas Goiran & Rayan Fakih & Nupur Bansal & Adelajda Hadzipasic & Jing Fang & Paramasivam Murugan & Shimin Chen & Edward A. Fon & Warren D. Hirst & , 2024. "Activation of parkin by a molecular glue," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Christophe M. Capelle & Séverine Ciré & Fanny Hedin & Maxime Hansen & Lukas Pavelka & Kamil Grzyb & Dimitrios Kyriakis & Oliver Hunewald & Maria Konstantinou & Dominique Revets & Vera Tslaf & Tainá M., 2023. "Early-to-mid stage idiopathic Parkinson’s disease shows enhanced cytotoxicity and differentiation in CD8 T-cells in females," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. A. M. Schonhoff & D. A. Figge & G. P. Williams & A. Jurkuvenaite & N. J. Gallups & G. M. Childers & J. M. Webster & D. G. Standaert & J. E. Goldman & A. S. Harms, 2023. "Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Zachary D. Wallen & Ayse Demirkan & Guy Twa & Gwendolyn Cohen & Marissa N. Dean & David G. Standaert & Timothy R. Sampson & Haydeh Payami, 2022. "Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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