Abstract
Backgroundα-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.ResultsIn 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.ConclusionsOur data indicate that α-synuclein aggregation spread by prion-like mechanisms through neural networks in mouse brains.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0088-8) contains supplementary material, which is available to authorized users.
Highlights
Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by appearance of Lewy bodies (LBs) and Lewy neurites (LNs) [1]. α-Synuclein is the major component of LBs and LNs, and is deposited in a hyperphosphorylated form in β-sheet-rich amyloid fibrils [2,3,4,5]
We showed that αsyn pathology induced tau and TDP-43 accumulation in WT mice, similar to that seen in DLB brains
We investigated the spread of αsyn pathology in brains of mice after unilateral injection of recombinant mouse αsyn fibrils into SN, Str, or EC
Summary
Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by appearance of Lewy bodies (LBs) and Lewy neurites (LNs) [1]. α-Synuclein (αsyn) is the major component of LBs and LNs, and is deposited in a hyperphosphorylated form in β-sheet-rich amyloid fibrils [2,3,4,5]. Α-Synuclein (αsyn) is the major component of LBs and LNs, and is deposited in a hyperphosphorylated form in β-sheet-rich amyloid fibrils [2,3,4,5]. It was reported that the mutations affect amyloid fibril formation in vitro, neurons and through which insoluble αsyn is transported to other neurons remain unknown. We showed that αsyn pathology induced tau and TDP-43 accumulation in WT mice, similar to that seen in DLB brains. This mouse model should be useful for elucidating mechanisms of disease progression of synucleinopathy and for development of novel disease-modifying drugs
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