Neuroinvasion of α-Synuclein Prionoids after Intraperitoneal and Intraglossal Inoculation

alpha-Synuclein is a soluble, cellular protein that in a number of neurodegenerative diseases, including Parkinson's disease and multiple system atrophy, forms pathological deposits of protein aggregates. Because misfolded alpha-synuclein has some characteristics that resemble those of prions, we investigated its potential to induce disease after intraperitoneal or intraglossal challenge injection into bigenic Tg(M83(+/-):Gfap-luc(+/-)) mice, which express the A53T mutant of human alpha-synuclein and firefly luciferase. After a single intraperitoneal injection with alpha-synuclein fibrils, four of five mice developed paralysis and alpha-synuclein pathology in the central nervous system, with a median incubation time of 229 +/- 17 days. Diseased mice accumulated aggregates of Sarkosyl-insoluble and phosphorylated alpha-synuclein in the brain and spinal cord, which colocalized with ubiquitin and p62 and were accompanied by gliosis. In contrast, only one of five mice developed alpha-synuclein pathology in the central nervous system after intraglossal injection with alpha-synuclein fibrils, after 285 days. These findings are novel and important because they show that, similar to prions, alpha-synuclein prionoids can neuroinvade the central nervous system after intraperitoneal or intraglossal injection and can cause neuropathology and disease. IMPORTANCE Synucleinopathies are neurodegenerative diseases that are characterized by the pathological presence of aggregated alpha-synuclein in cells of the nervous system. Previous studies have shown that alpha-synuclein aggregates made of recombinant protein or derived from brains of patients can spread in the central nervous system in a spatiotemporal manner when inoculated into the brains of animals and can induce pathology and neurologic disease, suggesting that misfolded alpha-synuclein can behave similarly to prions. Here we show that alpha-synuclein inoculation into the peritoneal cavity or the tongue in mice overexpressing alpha-synuclein causes neurodegeneration after neuroinvasion from the periphery, which further corroborates the prionoid character of misfolded alpha-synuclein.