Several age-related neurodegenerative disorders are characterized by the deposition of aberrantly folded proteins. The histopathological hallmark of synucleinopathies is the deposition of ɑ-synuclein (ɑSyn) protein in the central and peripheral nervous system and these pathological features are often associated with region-specific symptomatology. Symptoms in the urogenital organs, as well as urinary tract infections, 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 bacterial infection of the genitourinary tract causing ɑ-synuclein (ɑSyn) to aggregate in peripheral nerves innervating these organs. We show that bacterial infection of the urinary bladder can cause 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 infection, ɑSyn is released extracellularly from neutrophils as part of their extracellular traps. Chronic urinary tract infections aggravate ɑSyn pathology in humanized ɑSyn mice. Injection of human MSA aggregates into the urinary bladder leads to motor deficits and propagates ɑSyn pathology to the central nervous system in humanized mice overexpressing ɑSyn. With this work we link bacterial infections with synucleinopathy and show that a host response to environmental triggers can result in ɑSyn pathology that bears semblance to MSA.

Learning Objectives:

1. Define synucleinopathies and describe the histopathological hallmarks of multiple system atrophy.

2. Explain triggers of synucleinopathy and how peripheral triggers might propagate to the central nervous system.

3. Identify strategies to stop the progression of synucleinopathy.