The structure of dopamine induced α-synuclein oligomers (original) (raw)
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Proteins: Structure, Function, and Bioinformatics, 2014
Alpha-synuclein (a-syn) forms the amyloid-containing Lewy bodies found in the brain in Parkinson's disease. The neurotransmitter dopamine (DA) reacts with a-syn to form SDS-resistant soluble, non-amyloid, and melanin-containing oligomers. Their toxicity is debated, as is the nature of their structure and their relation to amyloid-forming conformers of a-syn. The small-angle X-ray scattering technique in combination with modeling by the ensemble optimization method showed that the un-reacted native protein populated three broad classes of conformer, while reaction with DA gave a restricted ensemble range suggesting that the rigid melanin molecule played an important part in their structure. We found that 6 M guanidine hydrochloride did not dissociate a-syn DA-reacted dimers and trimers, suggesting covalent linkages. The pathological significance of covalent association is that if they are non-toxic, the oligomers would act as a sink for toxic excess DA and a-syn; if toxic, their stability could enhance their toxicity. We argue it is essential, therefore, to resolve the question of whether they are toxic or not.
Structural and Biophysical Characterization of Stable Alpha-Synuclein Oligomers
International Journal of Molecular Sciences
The aggregation of α-synuclein (α-syn) into neurotoxic oligomers and fibrils is an important pathogenic feature of synucleinopatheis, including Parkinson’s disease (PD). A further characteristic of PD is the oxidative stress that results in the formation of aldehydes by lipid peroxidation. It has been reported that the brains of deceased patients with PD contain high levels of protein oligomers that are cross-linked to these aldehydes. Increasing evidence also suggests that prefibrillar oligomeric species are more toxic than the mature amyloid fibrils. However, due to the heterogenous and metastable nature, characterization of the α-syn oligomeric species has been challenging. Here, we generated and characterized distinct α-syn oligomers in vitro in the presence of DA and lipid peroxidation products 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE). HNE and ONE oligomer were stable towards the treatment with SDS, urea, and temperature. The secondary structure analysis revealed tha...
Dopamine quinones interact with α-synuclein to form unstructured adducts
Biochemical and Biophysical Research Communications, 2010
Oxidative stress Parkinson's disease a b s t r a c t a-Synuclein (asyn) fibril formation is considered a central event in the pathogenesis of Parkinson's disease (PD). In recent years, it has been proposed that prefibrillar annular oligomeric b-sheet-rich species, called protofibrils, rather than fibrils themselves, may be the neurotoxic species. The oxidation products of dopamine (DAQ) can inhibit asyn fibril formation supporting the idea that DAQ might stabilize asyn protofibrils.
Journal of neurochemistry, 2018
The amyloid aggregation of the presynaptic protein α-synuclein (AS) is pathognomonic of Parkinson's disease and other neurodegenerative disorders. Physiologically, AS contributes to synaptic homeostasis by participating in vesicle maintenance, trafficking and release. Its avidity for highly curved acidic membranes has been related to the distinct chemistry of the N-terminal amphipathic helix adopted upon binding to appropriated lipid interfaces. Pathologically, AS populate a myriad of toxic aggregates ranging from soluble oligomers to insoluble amyloid fibrils. Different gain-of-toxic function mechanisms are linked to prefibrillar oligomers which are considered as the most neurotoxic species. Here, we investigated if amyloid oligomerization could hamper AS function as a membrane curvature sensor. We used fluorescence correlation spectroscopy to quantitatively evaluate the interaction of oligomeric species, produced using a popular method based on lyophilization and rehydration, ...
The FASEB Journal, 2005
Dopamine (DA) and α-synuclein (α-SN) are two key molecules associated with Parkinson's disease (PD). We have identified a novel action of DA in the initial phase of α-SN aggregation and demonstrate that DA induces α-SN to form soluble, SDS-resistant oligomers. The DA:α-SN oligomeric species are not amyloidogenic as they do not react with thioflavin T and lack the typical amyloid fibril structures as visualized with electron microscopy. Circular dichroism studies indicate that in the presence of lipid membranes DA interacts with α-SN, causing an alteration to the structure of the protein. Furthermore, DA inhibited the formation of ironinduced α-SN amyloidogenic aggregates, suggesting that DA acts as a dominant modulator of α-SN aggregation. These observations support the paradigm emerging for other neurodegenerative diseases that the toxic species is represented by a soluble oligomer and not the insoluble fibril.
Dopamine-Induced Conformational Changes in Alpha-Synuclein
PLoS ONE, 2009
Background: Oligomerization and aggregation of a-synuclein molecules play a major role in neuronal dysfunction and loss in Parkinson's disease . However, a-synuclein oligomerization and aggregation have mostly been detected indirectly in cells using detergent extraction methods . A number of in vitro studies showed that dopamine can modulate the aggregation of a-synuclein by inhibiting the formation of or by disaggregating amyloid fibrils .
PLoS ONE, 2013
Amyloid fibrils of a-synuclein are the main constituent of Lewy bodies deposited in substantial nigra of Parkinson's disease brains. a-Synuclein is an intrinsically disordered protein lacking compact secondary and tertiary structures. To enhance the understanding of its structure and function relationship, we utilized temperature treatment to study a-synuclein conformational changes and the subsequent effects. We found that after 1 hr of high temperature pretreatment, .80uC, asynuclein fibrillization was significantly inhibited. However, the temperature melting coupled with circular dichroism spectra showed that a-synuclein was fully reversible and the NMR studies showed no observable structural changes of a-synuclein after 95uC treatment. By using cross-linking and analytical ultracentrifugation, rare amount of pre-existing a-synuclein oligomers were found to decrease after the high temperature treatment. In addition, a small portion of C-terminal truncation of a-synuclein also occurred. The reduction of pre-existing oligomers of a-synuclein may contribute to less seeding effect that retards the kinetics of amyloid fibrillization. Overall, our results showed that the pre-existing oligomeric species is a key factor contributing to a-synuclein fibrillization. Our results facilitate the understanding of a-synuclein fibrillization.
Biopolymers, 2006
a-Synuclein (a-Syn) has been identified as a component of intracellular fibrillar deposits in Parkinson's disease. Though the real pathogenesis is still unknown, many investigations have revealed that conformational alteration and fibril formation of a-Syn protein have an important role in causing the disease. In this work, we introduced the g-factor spectra of solid-state circular dichroism to estimate the secondary structure contents of a-Syn fragments in amyloids. Fourier-transform infrared (FTIR) was also applied to confirm the structural formation. The results suggest that the central hydrophobic region is critical for b-sheet formation and the conformational alteration is the foundation of protein abnormal aggregation. The research provides a practical approach to estimate the secondary structure contents of protein amyloids and further insight into the relevance of structural transformation and amyloidogenesis.
Journal of Molecular Biology, 2009
The deposition of α-synuclein (α-syn) aggregates in dopaminergic neurons is a key feature of Parkinson's disease. While dopamine (DA) can modulate α-syn aggregation, it is unclear which other factors can regulate the actions of DA on α-syn. In this study, we investigated the effect of solution conditions (buffer, salt and pH) on the oligomerization of α-syn by DA. We show that α-syn oligomerization is dependent on the oxidation of DA into reactive intermediates. Under acidic pH conditions, DA is stable, and DAmediated oligomerization of α-syn is inhibited. From pH 7.0 to pH 11.0, DA is unstable and undergoes redox reactions, promoting the formation of SDSresistant soluble oligomers of α-syn. We show that the reactive intermediate 5,6-dihydroxylindole mediates the formation of α-syn soluble oligomers under physiological conditions (pH 7.4). In contrast, under acidic conditions (pH 4.0), 5,6-dihydroxylindole promotes the formation of SDS-resistant insoluble oligomers that further associate to form sheet-like fibrils with βsheet structure that do not bind the dye thioflavin T. These results suggest that distinct reactive intermediates of DA, and not DA itself, interact with αsyn to generate the α-syn aggregates implicated in Parkinson's disease.