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Pathological alpha-synuclein propagates through neural networks

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-syn...

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Autores principales: Masuda-Suzukake, Masami, Nonaka, Takashi, Hosokawa, Masato, Kubo, Maki, Shimozawa, Aki, Akiyama, Haruhiko, Hasegawa, Masato
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147188/
https://www.ncbi.nlm.nih.gov/pubmed/25095794
http://dx.doi.org/10.1186/s40478-014-0088-8
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author Masuda-Suzukake, Masami
Nonaka, Takashi
Hosokawa, Masato
Kubo, Maki
Shimozawa, Aki
Akiyama, Haruhiko
Hasegawa, Masato
author_facet Masuda-Suzukake, Masami
Nonaka, Takashi
Hosokawa, Masato
Kubo, Maki
Shimozawa, Aki
Akiyama, Haruhiko
Hasegawa, Masato
author_sort Masuda-Suzukake, Masami
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-014-0088-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-41471882014-08-29 Pathological alpha-synuclein propagates through neural networks Masuda-Suzukake, Masami Nonaka, Takashi Hosokawa, Masato Kubo, Maki Shimozawa, Aki Akiyama, Haruhiko Hasegawa, Masato Acta Neuropathol Commun Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-014-0088-8) contains supplementary material, which is available to authorized users. BioMed Central 2014-08-06 /pmc/articles/PMC4147188/ /pubmed/25095794 http://dx.doi.org/10.1186/s40478-014-0088-8 Text en © Masuda-Suzukake et al.; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Masuda-Suzukake, Masami
Nonaka, Takashi
Hosokawa, Masato
Kubo, Maki
Shimozawa, Aki
Akiyama, Haruhiko
Hasegawa, Masato
Pathological alpha-synuclein propagates through neural networks
title Pathological alpha-synuclein propagates through neural networks
title_full Pathological alpha-synuclein propagates through neural networks
title_fullStr Pathological alpha-synuclein propagates through neural networks
title_full_unstemmed Pathological alpha-synuclein propagates through neural networks
title_short Pathological alpha-synuclein propagates through neural networks
title_sort pathological alpha-synuclein propagates through neural networks
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147188/
https://www.ncbi.nlm.nih.gov/pubmed/25095794
http://dx.doi.org/10.1186/s40478-014-0088-8
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