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Proaggregant nuclear factor(s) trigger rapid formation of ?-synuclein aggregates in apoptotic neurons.

ABSTRACT: Cell-to-cell transmission of ?-synuclein (?S) aggregates has been proposed to be responsible for progressive ?S 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 ?S aggregates can spread into surrounding cells and trigger PD-like pathology. It remains to be determined what factor(s) lead to initiation of ?S aggregation that is capable of seeding subsequent propagation. In this study we demonstrate that filamentous ?S 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 ?S and proaggregant nuclear factor(s) is associated with disruption of nuclear envelope integrity. Knocking down a key nuclear envelop constituent protein, lamin B1, enhances ?S 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 ?S aggregation might be related to neuronal apoptosis or loss of nuclear membrane integrity, exposing cytosolic ?-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 ?S aggregation, deposition, local uptake and subsequent propagation might significantly impact progression of disease.

SUBMITTER: Jiang P

PROVIDER: S-EPMC4911378 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Proaggregant nuclear factor(s) trigger rapid formation of α-synuclein aggregates in apoptotic neurons.

Jiang Peizhou P Gan Ming M Yen Shu-Hui SH Moussaud Simon S McLean Pamela J PJ Dickson Dennis W DW

Acta neuropathologica 20160202 1

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 ca ...[more]

PMID: 26839082

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Project description:Human studies and preclinical models of Parkinson's disease implicate the involvement of both the innate and adaptive immune systems in disease progression. Further, pro-inflammatory markers are highly enriched near neurons containing pathological forms of alpha synuclein (?-syn), and ?-syn overexpression recapitulates neuroinflammatory changes in models of Parkinson's disease. These data suggest that ?-syn may initiate a pathological inflammatory response, however the mechanism by which ?-syn initiates neuroinflammation is poorly understood. Silencing endogenous ?-syn results in a similar pattern of nigral degeneration observed following ?-syn overexpression. Here we aimed to test the hypothesis that loss of ?-syn function within nigrostriatal neurons results in neuronal dysfunction, which subsequently stimulates neuroinflammation. Adeno-associated virus (AAV) expressing an short hairpin RNA (shRNA) targeting endogenous ?-syn was unilaterally injected into the substantia nigra pars compacta (SNc) of adult rats, after which nigrostriatal pathology and indices of neuroinflammation were examined at 7, 10, 14 and 21 days post-surgery. Removing endogenous ?-syn from nigrostriatal neurons resulted in a rapid up-regulation of the major histocompatibility complex class 1 (MHC-1) within transduced nigral neurons. Nigral MHC-1 expression occurred prior to any overt cell death and coincided with the recruitment of reactive microglia and T-cells to affected neurons. Following the induction of neuroinflammation, ?-syn knockdown resulted in a 50% loss of nigrostriatal neurons in the SNc and a corresponding loss of nigrostriatal terminals and dopamine (DA) concentrations within the striatum. Expression of a control shRNA did not elicit any pathological changes. Silencing ?-syn within glutamatergic neurons of the cerebellum did not elicit inflammation or cell death, suggesting that toxicity initiated by ?-syn silencing is specific to DA neurons. These data provide evidence that loss of ?-syn function within nigrostriatal neurons initiates a neuronal-mediated neuroinflammatory cascade, involving both the innate and adaptive immune systems, which ultimately results in the death of affected neurons.

Dataset Information

Proaggregant nuclear factor(s) trigger rapid formation of ?-synuclein aggregates in apoptotic neurons.

Publications

Proaggregant nuclear factor(s) trigger rapid formation of α-synuclein aggregates in apoptotic neurons.

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