Urinary tract infections trigger synucleinopathy via the innate immune response.
Acta Neuropathol
; 145(5): 541-559, 2023 05.
Article
in En
| MEDLINE
| ID: mdl-36991261
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 É-synuclein (ÉSyn) 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 ÉSyn in the innate immune system response to bacteria. Urinary tract infection with uropathogenic E. coli results in the de novo aggregation of ÉSyn during neutrophil infiltration. During the infection, ÉSyn 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 ÉSyn pathology to the central nervous system in mice overexpressing oligodendroglial ÉSyn. 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 ÉSyn pathology that bears semblance to MSA.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Urinary Tract Infections
/
Multiple System Atrophy
/
Synucleinopathies
Type of study:
Observational_studies
/
Risk_factors_studies
Limits:
Animals
Language:
En
Journal:
Acta Neuropathol
Year:
2023
Type:
Article
Affiliation country:
United States