title: Pathological alpha-synuclein propagates through neural networks.
abstract: BACKGROUND
  α-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 α-synucleinopathies. Recent studies revealed that intracerebral injection of recombinant α-synuclein fibrils into wild-type mouse brains induced prion-like propagation of hyperphosphorylated α-synuclein pathology. However, the propagation mechanisms of α-synuclein have not been fully elucidated.
  
  
  RESULTS
  In this study, in order to establish where and how α-synuclein pathology propagates, we injected recombinant mouse α-synuclein fibrils into three different brain areas (substantia nigra, striatum, and entorhinal cortex) of wild-type mice and compared the resulting distributions of α-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 α-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 α-synuclein pathology. It seems that accumulation of α-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 α-synuclein fibrils can also induce phosphorylated α-synuclein pathology in wild-type mice.
  
  
  CONCLUSIONS
  Our data indicate that α-synuclein aggregation spread by prion-like mechanisms through neural networks in mouse brains.
authors.forename: Masami
authors.initials: M
authors.lastname: Masuda-Suzukake
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.forename: Masato
authors.initials: M
authors.lastname: Hosokawa
authors.forename: Maki
authors.initials: M
authors.lastname: Kubo
authors.forename: Aki
authors.initials: A
authors.lastname: Shimozawa
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku 156-0057, Tokyo, Japan. hasegawa-ms@igakuken.or.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D011328:Prions / Q000378:metabolism; D011994:Recombinant Proteins / Q000633:toxicity; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D016875:tau Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D011328:Prions; D011994:Recombinant Proteins; D051844:alpha-Synuclein; D016875:tau Proteins; C497605:Snca protein, mouse; C578077:Tardbp protein, mouse
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