title: Prion-like spreading of pathological α-synuclein in brain.
abstract: α-Synuclein is the major component of filamentous inclusions that constitute the defining characteristic of neurodegenerative α-synucleinopathies. However, the molecular mechanisms underlying α-synuclein accumulation and spread are unclear. Here we show that intracerebral injections of sarkosyl-insoluble α-synuclein from brains of patients with dementia with Lewy bodies induced hyperphosphorylated α-synuclein pathology in wild-type mice. Furthermore, injection of fibrils of recombinant human and mouse α-synuclein efficiently induced similar α-synuclein pathologies in wild-type mice. C57BL/6J mice injected with α-synuclein fibrils developed abundant Lewy body/Lewy neurite-like pathology, whereas mice injected with soluble α-synuclein did not. Immunoblot analysis demonstrated that endogenous mouse α-synuclein started to accumulate 3 months after inoculation, while injected human α-synuclein fibrils disappeared in about a week. These results indicate that α-synuclein fibrils have prion-like properties and inoculation into wild-type brain induces α-synuclein pathology in vivo. This is a new mouse model of sporadic α-synucleinopathy and should be useful for elucidating progression mechanisms and evaluating disease-modifying therapy.
authors: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors: Masami
authors: M
authors: Masuda-Suzukake
authors: Takashi
authors: T
authors: Nonaka
authors: Masato
authors: M
authors: Hosokawa
authors: Takayuki
authors: T
authors: Oikawa
authors: Tetsuaki
authors: T
authors: Arai
authors: Haruhiko
authors: H
authors: Akiyama
authors: David M A
authors: DM
authors: Mann
authors: Masato
authors: M
authors: Hasegawa
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007276:Injections, Intraventricular; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011328:Prions / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000633:toxicity; D013997:Time Factors; D051844:alpha-Synuclein / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity
chemical_list: D011328:Prions; D011994:Recombinant Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051844:alpha-Synuclein