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Prion-like spreading of pathological ?-synuclein in brain.

ABSTRACT: ?-Synuclein is the major component of filamentous inclusions that constitute the defining characteristic of neurodegenerative ?-synucleinopathies. However, the molecular mechanisms underlying ?-synuclein accumulation and spread are unclear. Here we show that intracerebral injections of sarkosyl-insoluble ?-synuclein from brains of patients with dementia with Lewy bodies induced hyperphosphorylated ?-synuclein pathology in wild-type mice. Furthermore, injection of fibrils of recombinant human and mouse ?-synuclein efficiently induced similar ?-synuclein pathologies in wild-type mice. C57BL/6J mice injected with ?-synuclein fibrils developed abundant Lewy body/Lewy neurite-like pathology, whereas mice injected with soluble ?-synuclein did not. Immunoblot analysis demonstrated that endogenous mouse ?-synuclein started to accumulate 3 months after inoculation, while injected human ?-synuclein fibrils disappeared in about a week. These results indicate that ?-synuclein fibrils have prion-like properties and inoculation into wild-type brain induces ?-synuclein pathology in vivo. This is a new mouse model of sporadic ?-synucleinopathy and should be useful for elucidating progression mechanisms and evaluating disease-modifying therapy.

SUBMITTER: Masuda-Suzukake M

PROVIDER: S-EPMC3613715 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Prion-like spreading of pathological α-synuclein in brain.

Masuda-Suzukake Masami M Nonaka Takashi T Hosokawa Masato M Oikawa Takayuki T Arai Tetsuaki T Akiyama Haruhiko H Mann David M A DM Hasegawa Masato M

Brain : a journal of neurology 20130306 Pt 4

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 ...[more]

PMID: 23466394

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Project description:BackgroundThe accumulation of misfolded proteins appears as a fundamental pathogenic process in human neurodegenerative diseases. In the case of synucleinopathies such as Parkinson's disease (PD) or dementia with Lewy bodies (DLB), the intraneuronal deposition of aggregated alpha-synuclein (?S) is a major characteristic of the disease, but the molecular basis distinguishing the disease-associated protein (?SD) from its normal counterpart remains poorly understood. However, recent research suggests that a prion-like mechanism could be involved in the inter-cellular and inter-molecular propagation of aggregation of the protein within the nervous system.ResultsOur data confirm our previous observations of disease acceleration in a transgenic mouse line (M83) overexpressing a mutated (A53T) form of human ?S, following inoculation of either brain extracts from sick M83 mice or fibrillar recombinant ?S. A similar phenomenon is observed following a "second passage" in the M83 mouse model, including after stereotactic inoculations into the hippocampus or cerebellum. For further molecular analyses of ?SD, we designed an ELISA test that identifies ?SD specifically in sick mice and in the brain regions targeted by the pathological process in this mouse model. ?SD distribution, mainly in the caudal brain regions and spinal cord, overall appears remarkably uniform, whatever the conditions of experimental challenge. In addition to specific detection of ?SD immunoreactivity using an antibody against Ser129 phosphorylated ?S, similar results were observed in ELISA with several other antibodies against the C-terminal part of ?S, including an antibody against non phosphorylated ?S. This also indicated consistent immunoreactivity of the murine ?S protein specifically in the affected brain regions of sick mice.ConclusionsPrion-like behaviour in propagation of the disease-associated ?S was confirmed with the M83 transgenic mouse model, that could be followed by an ELISA test. The ELISA data question their possible relationship with the conformational differences between the disease-associated ?S and its normal counterpart.

Dataset Information

Prion-like spreading of pathological ?-synuclein in brain.

Publications

Prion-like spreading of pathological α-synuclein in brain.

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