Pathological alpha-synuclein propagates through neural networks

Background: alpha-Synuclein is the major component of filamentous inclusions that constitute the defining characteristic of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, so-called alpha-synucleinopathies. Recent studies revealed that intracerebral injection of recombinant alpha-synuclein fibrils into wild-type mouse brains induced prion-like propagation of hyperphosphorylated alpha-synuclein pathology. However, the propagation mechanisms of alpha-synuclein have not been fully elucidated. Results: In this study, in order to establish where and how alpha-synuclein pathology propagates, we injected recombinant mouse alpha-synuclein fibrils into three different brain areas (substantia nigra, striatum, and entorhinal cortex) of wild-type mice and compared the resulting distributions of alpha-synuclein pathology at 1 month after injection. Distinct patterns of pathology were observed in mice injected at the different sites. Within one month after injection, the pathology had spread to neurons in areas far from the injection sites, especially areas with direct neural connections to the injection sites. Surprisingly, phosphorylated tau and TDP-43 pathologies were also observed in mice injected with alpha-synuclein fibrils into striatum and entorhinal cortex at one month after injection. Phosphorylated tau and TDP-43 were accumulated in dot-like inclusions, but these were rarely colocalized with alpha-synuclein pathology. It seems that accumulation of alpha-synuclein has a synergistic effect on tau and TDP-43 aggregation. Additionally, intracerebral injection with sarkosyl-insoluble fraction prepared from wild-type mice injected synthetic alpha-synuclein fibrils can also induce phosphorylated alpha-synuclein pathology in wild-type mice. Conclusions: Our data indicate that alpha-synuclein aggregation spread by prion-like mechanisms through neural networks in mouse brains.