Abstract
Cell-to-cell transmission of α-synuclein (αS) aggregates has been proposed to be responsible for progressive αS pathology in Parkinson disease (PD) and related disorders, including dementia with Lewy bodies. In support of this concept, a growing body of in vitro and in vivo experimental evidence shows that exogenously introduced αS aggregates can spread into surrounding cells and trigger PD-like pathology. It remains to be determined what factor(s) lead to initiation of αS aggregation that is capable of seeding subsequent propagation. In this study we demonstrate that filamentous αS aggregates form in neurons in response to apoptosis induced by staurosporine or other toxins-6-hydroxy-dopamine and 1-methyl-4-phenylpyridinium (MPP+). Interaction between αS and proaggregant nuclear factor(s) is associated with disruption of nuclear envelope integrity. Knocking down a key nuclear envelop constituent protein, lamin B1, enhances αS aggregation. Moreover, in vitro and in vivo experimental models demonstrate that aggregates released upon cell breakdown can be taken up by surrounding cells. Accordingly, we suggest that at least some αS aggregation might be related to neuronal apoptosis or loss of nuclear membrane integrity, exposing cytosolic α-synuclein to proaggregant nuclear factors. These findings provide new clues to the pathogenesis of PD and related disorders that can lead to novel treatments of these disorders. Specifically, finding ways to limit the effects of apoptosis on αS aggregation, deposition, local uptake and subsequent propagation might significantly impact progression of disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1542-4) contains supplementary material, which is available to authorized users.
Highlights
Neuronal intracellular aggregates of α-synuclein in Lewy bodies and Lewy neurites are pathological features of Parkinson’s disease (PD) and related synucleinopathies such as dementia with Lewy bodies [1]
Pretreatment with a caspase inhibitor (CI)-Z-VAD-FMK, a cell-permeant pancaspase inhibitor that irreversibly binds to the catalytic site of caspase proteases, significantly reduced both caspase activation and αS aggregation (Fig. 1c, e), confirming that apoptosis contributes to formation of αS aggregates
Our study suggests that neuronal αS aggregation may be triggered in some cases by proaggregant nuclear factor(s) associated with apoptosis
Summary
Neuronal intracellular aggregates of α-synuclein (αS) in Lewy bodies and Lewy neurites are pathological features of Parkinson’s disease (PD) and related synucleinopathies such as dementia with Lewy bodies [1]. The mechanisms underlying αS pathology remain unclear, the possibility that abnormal conformers of αS may propagate from one cell to another has drawn increasing attention [2, 3]. A growing body of in vivo and in vitro experimental evidence supports the possibility that αS can spread from cell to cell [7,8,9,10,11]. Inherent to this hypothesis is initial formation of “seeds” of abnormal αS in selectively vulnerable neuronal populations, which subsequently propagate [3, 12]. The origin of the seeds in experimental studies has been abnormal conformers of recombinant wild-type or
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