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Urinary tract infections trigger synucleinopathy via the innate immune response.
Peelaerts, Wouter; Mercado, Gabriela; George, Sonia; Villumsen, Marie; Kasen, Alysa; Aguileta, Miguel; Linstow, Christian; Sutter, Alexandra B; Kuhn, Emily; Stetzik, Lucas; Sheridan, Rachel; Bergkvist, Liza; Meyerdirk, Lindsay; Lindqvist, Allison; Gavis, Martha L Escobar; Van den Haute, Chris; Hultgren, Scott J; Baekelandt, Veerle; Pospisilik, J Andrew; Brudek, Tomasz; Aznar, Susana; Steiner, Jennifer A; Henderson, Michael X; Brundin, Lena; Ivanova, Magdalena I; Hannan, Tom J; Brundin, Patrik.
Afiliación
  • Peelaerts W; Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, MI, USA.
  • Mercado G; Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Louvain, Belgium.
  • George S; Laboratory for Virology and Gene Therapy, Department of Pharmacy and Pharmaceutical Sciences, KU Leuven, Louvain, Belgium.
  • Villumsen M; Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, MI, USA.
  • Kasen A; Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, MI, USA.
  • Aguileta M; Center for Clinical Research and Disease Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
  • Linstow C; Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, MI, USA.
  • Sutter AB; Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, MI, USA.
  • Kuhn E; Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, MI, USA.
  • Stetzik L; Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
  • Sheridan R; Neuroscience Graduate Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • Bergkvist L; Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, MI, USA.
  • Meyerdirk L; Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, MI, USA.
  • Lindqvist A; Flow Cytometry Core Facility, Van Andel Institute, Grand Rapids, MI, USA.
  • Gavis MLE; Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, MI, USA.
  • Van den Haute C; Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, MI, USA.
  • Hultgren SJ; Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, MI, USA.
  • Baekelandt V; Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, MI, USA.
  • Pospisilik JA; Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Louvain, Belgium.
  • Brudek T; Leuven Viral Vector Core, Department of Neurosciences, KU Leuven, Louvain, Belgium.
  • Aznar S; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  • Steiner JA; Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Louvain, Belgium.
  • Henderson MX; Leuven Viral Vector Core, Department of Neurosciences, KU Leuven, Louvain, Belgium.
  • Brundin L; Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
  • Ivanova MI; Centre for Neuroscience and Stereology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
  • Hannan TJ; Centre for Neuroscience and Stereology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
  • Brundin P; Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, MI, USA.
Acta Neuropathol ; 145(5): 541-559, 2023 05.
Article en En | MEDLINE | ID: mdl-36991261
Symptoms in the urogenital organs are common in multiple system atrophy (MSA), also in the years preceding the MSA diagnosis. It is unknown how MSA is triggered and these observations in prodromal MSA led us to hypothesize that synucleinopathy could be triggered by infection of the genitourinary tract causing ɑ-synuclein (ɑSyn) to aggregate in peripheral nerves innervating these organs. As a first proof that peripheral infections could act as a trigger in MSA, this study focused on lower urinary tract infections (UTIs), given the relevance and high frequency of UTIs in prodromal MSA, although other types of infection might also be important triggers of MSA. We performed an epidemiological nested-case control study in the Danish population showing that UTIs are associated with future diagnosis of MSA several years after infection and that it impacts risk in both men and women. Bacterial infection of the urinary bladder triggers synucleinopathy in mice and we propose a novel role of ɑSyn in the innate immune system response to bacteria. Urinary tract infection with uropathogenic E. coli results in the de novo aggregation of ɑSyn during neutrophil infiltration. During the infection, ɑSyn is released extracellularly from neutrophils as part of their extracellular traps. Injection of MSA aggregates into the urinary bladder leads to motor deficits and propagation of ɑSyn pathology to the central nervous system in mice overexpressing oligodendroglial ɑSyn. Repeated UTIs lead to progressive development of synucleinopathy with oligodendroglial involvement in vivo. Our results link bacterial infections with synucleinopathy and show that a host response to environmental triggers can result in ɑSyn pathology that bears semblance to MSA.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Infecciones Urinarias / Atrofia de Múltiples Sistemas / Sinucleinopatías Tipo de estudio: Observational_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Acta Neuropathol Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Infecciones Urinarias / Atrofia de Múltiples Sistemas / Sinucleinopatías Tipo de estudio: Observational_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Acta Neuropathol Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania