| First Author | Breid S | Year | 2016 |
| Journal | J Virol | Volume | 90 |
| Issue | 20 | Pages | 9182-93 |
| PubMed ID | 27489279 | Mgi Jnum | J:236004 |
| Mgi Id | MGI:5804458 | Doi | 10.1128/JVI.01399-16 |
| Citation | Breid S, et al. (2016) Neuroinvasion of alpha-Synuclein Prionoids after Intraperitoneal and Intraglossal Inoculation. J Virol 90(20):9182-93 |
| abstractText | 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. |
