Urinary tract infections trigger synucleinopathy via the innate immune response

Wouter Peelaerts, Gabriela Mercado, Sonia George, Marie Villumsen, Alysa Kasen, Miguel Aguileta, Christian Linstow, Alexandra B. Sutter, Emily Kuhn, Lucas Stetzik, Rachel Sheridan, Liza Bergkvist, Lindsay Meyerdirk, Allison Lindqvist, Martha L.Escobar Gavis, Chris Van den Haute, Scott J. Hultgren, Veerle Baekelandt, J. Andrew Pospisilik, Tomasz BrudekSusana Aznar, Jennifer A. Steiner, Michael X. Henderson, Lena Brundin, Magdalena I. Ivanova, Tom J. Hannan, Patrik Brundin

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)541-559
Number of pages19
JournalActa neuropathologica
Volume145
Issue number5
DOIs
StatePublished - May 2023
Externally publishedYes

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Pathology and Forensic Medicine

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