| First Author | Woerman AL | Year | 2020 |
| Journal | PLoS Pathog | Volume | 16 |
| Issue | 2 | Pages | e1008222 |
| PubMed ID | 32017806 | Mgi Jnum | J:292673 |
| Mgi Id | MGI:6435619 | Doi | 10.1371/journal.ppat.1008222 |
| Citation | Woerman AL, et al. (2020) Kinetics of alpha-synuclein prions preceding neuropathological inclusions in multiple system atrophy. PLoS Pathog 16(2):e1008222 |
| abstractText | Multiple system atrophy (MSA), a progressive neurodegenerative disease characterized by autonomic dysfunction and motor impairment, is caused by the self-templated misfolding of the protein alpha-synuclein. With no treatment currently available, we sought to characterize the spread of alpha-synuclein in a transgenic mouse model of MSA prion propagation to support drug discovery programs for synucleinopathies. Brain homogenates from MSA patient samples or mouse-passaged MSA were inoculated either by standard freehand injection or stereotactically into TgM83+/- mice, which express human alpha-synuclein with the A53T mutation. Following disease onset, brains from the mice were tested for biologically active alpha-synuclein prions using a cell-based assay and examined for alpha-synuclein neuropathology. Inoculation studies using homogenates prepared from brain regions lacking detectable alpha-synuclein neuropathology transmitted neurological disease to mice. Terminal animals contained similar concentrations of alpha-synuclein prions; however, a time-course study where mice were terminated every five days through disease progression revealed that the kinetics of alpha-synuclein prion replication in the mice were variable. Stereotactic inoculation into the thalamus reduced variability in disease onset in the mice, although incubation times were consistent with standard inoculations. Using human samples with and without neuropathological lesions, we observed that alpha-synuclein prion formation precedes neuropathology in the brain, suggesting that disease in patients is not limited to brain regions containing neuropathological lesions. |
