Article, 2023
Urinary tract infections trigger synucleinopathy via the innate immune response
Acta Neuropathologica,
ISSN
0001-6322,
1432-0533,
Volume 145,
5,
Pages 541-559,
10.1007/s00401-023-02562-4
Contributors
Peelaerts, Wouter
0000-0003-3776-4162
[1]
[2]
Mercado, Gabriela
0000-0002-3346-5758
[2]
George, Sonia
[2]
Villumsen, Marie
0000-0001-8454-4686
[3]
Kasen, Alysa
[2]
Aguileta, Miguel-Angel
[2]
Linstow, Christian
[2]
Sutter, Alexandra B
0000-0003-1410-8605
[4]
[5]
Kuhn, Emily
[2]
Stetzik, Lucas A
[2]
Sheridan, Rachel
[2]
Bergkvist, Liza
0000-0001-7433-2647
[2]
Meyerdirk, Lindsay K
[2]
Lindqvist, Allison
[2]
Gavis, Martha L. Escobar
[2]
Van den Haute, Chris
[1]
Hultgren, Scott J
[6]
Baekelandt, Veerle
0000-0001-8966-2921
[1]
Pospisilik, John Andrew
[2]
Brudek, Tomasz
0000-0001-5453-1817
[3]
Aznar, Susana
0000-0001-7940-6246
[3]
Steiner, Jennifer A
0000-0003-0953-1310
[2]
Henderson, Michael X
0000-0001-9710-0726
[2]
Brundin, Lena Cecilia
0000-0002-8327-6242
[2]
Ivanova, Magdalena I
[4]
[5]
Hannan, Tom J.
[6]
Brundin, Patrik-
(Corresponding author)
[2]
[7]
Affiliations
- [1]
KU Leuven
[NORA names:
Belgium; Europe, EU; OECD];
- [2]
Van Andel Institute
[NORA names:
United States; America, North; OECD];
- [3]
Bispebjerg and Frederiksberg Hospital
[NORA names:
Capital Region of Denmark; Hospital; Denmark; Europe, EU; Nordic; OECD];
- [4]
Northwestern University
[NORA names:
United States; America, North; OECD];
- [5]
University of Michigan–Ann Arbor
[NORA names:
United States; America, North; OECD];
(... more)
- [6]
Washington University in St. Louis
[NORA names:
United States; America, North; OECD];
- [7]
Roche (Switzerland)
[NORA names:
Switzerland; Europe, Non-EU; OECD]
(less)
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.
Keywords
Danish population,
MSA diagnosis,
Prodromal multiple system atrophy,
Repeated urinary tract infections,
a-synuclein,
aSyn,
aSyn pathology,
aggregation,
aggregation of aSyn,
associated with future diagnosis,
atrophy,
bacteria,
bacterial infections,
bladder,
central nervous system,
controlled studies,
de novo aggregation,
deficits,
development of synucleinopathies,
diagnosis,
environmental triggers,
extracellular traps,
frequency,
frequency of urinary tract infections,
future diagnosis,
genitourinary tract,
host,
immune response,
impact risk,
infection,
infiltration,
injection,
innate immune response,
involvement in vivo,
men,
mice,
motor,
motor deficits,
multiple system atrophy,
nerve,
nervous system,
nested-case control study,
neutrophil infiltration,
neutrophils,
observations,
organization,
pathology,
peripheral infection,
peripheral nerves,
population,
progressive development,
propagation,
relevance,
response,
response to bacteria,
response to environmental triggers,
results,
risk,
semblance,
several years,
study,
symptoms,
synucleinopathies,
system,
system atrophy,
tract,
tract infections,
traps,
trigger,
triggered by infection,
urinary bladder,
urinary tract infection,
urogenital organs,
women,
years
Funders
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