Dopamine promotes formation and secretion of non-fibrillar alpha-synuclein oligomers

Lee, He Jin; Baek, Suji; Ho, Dong Hwan; Suk, Ji Eun; Cho, Eun Duk; Lee, Seung-Jae

doi:10.3858/emm.2011.43.4.026

Cited by 123 publications

(112 citation statements)

References 30 publications

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“…Finally, α-syn oligomers were produced by coincubation of monomeric α-syn with excess dopamine. [29][30][31] Under these conditions,~50% of monomeric α-syn was converted to oligomers after 4 days, as assessed by size exclusion chromatography (SEC) (Figure 1h). The purity, heterogeneity and amyloidogenic properties of α-syn oligomers were assessed by SEC, SDS-PAGE electrophoresis, TEM and ThT binding assay (Figures 1h-k).…”

Section: Resultsmentioning

confidence: 99%

Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death

et al. 2015

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The role of extracellular α-synuclein (α-syn) in the initiation and the spreading of neurodegeneration in Parkinson's disease (PD) has been studied extensively over the past 10 years. However, the nature of the α-syn toxic species and the molecular mechanisms by which they may contribute to neuronal cell loss remain controversial. In this study, we show that fully characterized recombinant monomeric, fibrillar or stabilized forms of oligomeric α-syn do not trigger significant cell death when added individually to neuroblastoma cell lines. However, a mixture of preformed fibrils (PFFs) with monomeric α-syn becomes toxic under conditions that promote their growth and amyloid formation. In hippocampal primary neurons and ex vivo hippocampal slice cultures, α-syn PFFs are capable of inducing a moderate toxicity over time that is greatly exacerbated upon promoting fibril growth by addition of monomeric α-syn. The causal relationship between α-syn aggregation and cellular toxicity was further investigated by assessing the effect of inhibiting fibrillization on α-syn-induced cell death. Remarkably, our data show that blocking fibril growth by treatment with known pharmacological inhibitor of α-syn fibrillization (Tolcapone) or replacing monomeric α-syn by monomeric β-synuclein in α-syn mixture composition prevent α-syn-induced toxicity in both neuroblastoma cell lines and hippocampal primary neurons. We demonstrate that exogenously added α-syn fibrils bind to the plasma membrane and serve as nucleation sites for the formation of α-syn fibrils and promote the accumulation and internalization of these aggregates that in turn activate both the extrinsic and intrinsic apoptotic cell death pathways in our cellular models. Our results support the hypothesis that ongoing aggregation and fibrillization of extracellular α-syn play central roles in α-syn extracellular toxicity, and suggest that inhibiting fibril growth and seeding capacity constitute a viable strategy for protecting against α-syn-induced toxicity and slowing the progression of neurodegeneration in PD and other synucleinopathies. 1 Nevertheless, the relationship between α-syn aggregation and neurodegeneration in PD remains elusive. 2A possible role for extracellular α-syn in the pathogenicity of PD emerged from the observation that newly grafted neurons in PD patients exhibit α-syn pathology similar to that of neighboring diseased cells. 3,4 Despite the consensus that α-syn is mainly an intracellular protein, α-syn has been detected in the cerebrospinal fluid under both pathological and healthy conditions. 5 In addition, in vivo rodent models and cellular studies have shown that monomers 6 and aggregated forms 6,7 of α-syn are secreted into the extracellular space via several mechanisms, 7,8 including the nonclassical endoplasmic reticulum/Golgi-independent exocytosis 8 or the exosomal route, 9,10 and are then internalized by neighboring cells. 7This suggests that extracellular α-syn may play a critical role in the spreading of α-syn pathology throughout the brai...

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Section: Resultsmentioning

confidence: 99%

Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death

et al. 2015

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“…In the presence of dopamine, recombinant human ␣-synuclein produces nonfibrillar, SDSresistant oligomers, whereas ␤-sheet-rich fibril formation is inhibited. Pharmacologic elevation of the cytoplasmic dopamine level increased the formation of SDS-resistant oligomers in DA-producing neuronal cells (49). Thus, in this case, neurotransmitter signaling appears to regulate peptide oligomerization and secretion of ␣-synuclein oligomers.…”

Section: Discussionmentioning

confidence: 90%

Erythrocytic Stage-dependent Regulation of Oligomerization of Plasmodium Ribosomal Protein P2

Sudarsan

Sivakami

et al. 2012

Journal of Biological Chemistry

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Background: Plasmodium falciparum P2 (PfP2) protein plays nonribosomal roles through SDS-and DTT-resistant oligomerization. Results: For SDS-and DTT-sensitive oligomerization, the 53rd cysteine of PfP2 plays an important role. Conclusion: DTT-and SDS-resistant oligomerization of PfP2 was propagated by differentially expressed parasite proteins. Significance: Analysis of regulation of PfP2 oligomerization in parasite-infected erythrocytes may help in understanding the export of P2 to erythrocyte surface.

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“…It has been reported that dopamine accelerates the α-synuclein oligomerization in intracellular vesicles and promotes the production of extracellular α-synuclein [46], which may contribute to the progressive loss of the dopaminergic neuronal population in the SNpc in the PD patients.…”

Section: The Extracellular α-Synuclein and Parkinson's Diseasementioning

confidence: 99%

The Extracellular α-Synuclein and its Biological Significance

Guo¹,

Zhen²

2013

Biochem & Pharmacol

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Abstractα-synuclein plays an important role in the development of Parkinson's disease (PD). It was believed that α-synuclein elicits its effects in the neuronal cytosol. However, the finding of extracellular α-synuclein expands the orthodox spectrum. The α-synuclein can be secreted via the multi-vesicle bodies-mediated exosome and the recycling-endosome pathway. In the intercellular milieu, the secreted α-synuclein is degraded by enzymes or engulfed by neighboring cells. The remaining α-synuclein can induce the neurotoxicity, activate microglia, and promote the pathogenesis of Parkinson's disease. In the review, we focus on the recent findings of extracellular α-synuclein and its biological significance.

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Dopamine promotes formation and secretion of non-fibrillar alpha-synuclein oligomers

Cited by 123 publications

References 30 publications

Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death

Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death

Erythrocytic Stage-dependent Regulation of Oligomerization of Plasmodium Ribosomal Protein P2

The Extracellular α-Synuclein and its Biological Significance

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