Dopamine promotes α‐synuclein aggregation into SDS‐resistant soluble oligomers via a distinct folding pathway

Cappai, Roberto; Leck, Su-Ling; Tew, Deborah J.; Williamson, Nicholas A.; Smith, David P.; Galatis, Denise; Sharples, Robyn A.; Curtain, Cyril C.; Ali, Feda E.; Cherny, Robert A.; Culvenor, Janetta G.; Bottomley, Stephen P.; Masters, Colin L.; Barnham, Kevin J.; Hill, Andrew F.

doi:10.1096/fj.04-3437fje

Cited by 246 publications

(276 citation statements)

References 46 publications

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“…The pattern of the oligomeric bands obtained from SDS/PAGE was consistent with previous work (Fig. 1A) (18,19), in which dimer, trimer, and higher molecular weight oligomers were observed. In contrast, without dopamine, α-Syn produced no oligomeric species (Fig.…”

Section: Resultssupporting

confidence: 91%

“…Soluble SDS-resistant large α-Syn oligomers were generated by incubating α-Syn (10 μM) in the presence of 10-fold molar excess amounts of dopamine (100 μM) at 37°C for 72 h (17)(18)(19). The pattern of the oligomeric bands obtained from SDS/PAGE was consistent with previous work (Fig.…”

Section: Resultssupporting

confidence: 87%

“…This observation led to the conjecture that dopamine, particularly its oxidant forms generated by oxidative stress, may play an important role in PD (11,15,16). Indeed, Conway et al (17) have shown that dopamine accelerates formation of large α-Syn oligomers while suppressing fibril formation, demonstrating the connection between dopamine and large α-Syn oligomers (18)(19)(20)(21). However, the molecular origin of the toxicity of dopamine-induced large α-Syn oligomers remains unclear (15,22).…”

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confidence: 99%

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Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking

Choi

Kim

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

246

237

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Parkinson disease and dementia with Lewy bodies are featured with the formation of Lewy bodies composed mostly of α-synuclein (α-Syn) in the brain. Although evidence indicates that the large oligomeric or protofibril forms of α-Syn are neurotoxic agents, the detailed mechanisms of the toxic functions of the oligomers remain unclear. Here, we show that large α-Syn oligomers efficiently inhibit neuronal SNARE-mediated vesicle lipid mixing. Large α-Syn oligomers preferentially bind to the N-terminal domain of a vesicular SNARE protein, synaptobrevin-2, which blocks SNARE-mediated lipid mixing by preventing SNARE complex formation. In sharp contrast, the α-Syn monomer has a negligible effect on lipid mixing even with a 30-fold excess compared with the case of large α-Syn oligomers. Thus, the results suggest that large α-Syn oligomers function as inhibitors of dopamine release, which thus provides a clue, at the molecular level, to their neurotoxicity.

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Section: Resultssupporting

confidence: 91%

Section: Resultssupporting

confidence: 87%

mentioning

confidence: 99%

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Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking

Choi

Kim

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

246

237

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“…In addition, coexpression of human ␣-syn with G proteinreceptor kinase 5 (GRK5), one of several kinases that is capable of phosphorylating Ser-129 (14,20), increased the formation of ␣-syn aggregates in cultured cells (21). In another study, coexpression of synphilin 1 with the S129A mutation of ␣-syn in cultured cells reduced aggregation and interaction with synphilin 1 (22), another component found in Lewy bodies. Finally, expression of S129D ␣-syn in cultured cells produced an increase of ubiquitinated ␣-syn conjugates and aggregate formation compared with wt ␣-syn (16,23).…”

Section: Discussionmentioning

confidence: 98%

The phosphorylation state of Ser-129 in human α-synuclein determines neurodegeneration in a rat model of Parkinson disease

Gorbatyuk

Sullivan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

259

226

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Studies have shown that ␣-synuclein (␣-syn) deposited in Lewy bodies in brain tissue from patients with Parkinson disease (PD) is extensively phosphorylated at Ser-129. We used recombinant Adeno-associated virus (rAAV) to overexpress human wild-type (wt) ␣-syn and two human ␣-syn mutants with site-directed replacement of Ser-129 to alanine (S129A) or to aspartate (S129D) in the nigrostriatal tract of the rat to investigate the effect of Ser-129 phosphorylation state on dopaminergic neuron pathology. Rats were injected with rAAV2/5 vectors in the substantia nigra pars compacta (SNc) on one side of the brain; the other side remained as a nontransduced control. The level of human wt or mutant ␣-syn expressed on the injected side was about four times the endogenous rat ␣-syn. There was a significant reduction of dopaminergic neurons in the SNc and dopamine (DA) and tyrosine hydroxylase (TH) levels in the striatum of all S129A-treated rats as early as 4 wk postinjection. Nigral DA pathology occurred more slowly in the wt-injected animals, but by 26 wk the wt ␣-syn group lost nigral TH neurons equivalent to the mutated S129A group at 8 wk. In stark contrast, we did not observe any pathological changes in S129D-treated animals. Therefore, the nonphosphorylated form of S129 exacerbates ␣-syn-induced nigral pathology, whereas Ser-129 phosphorylation eliminates ␣-syn-induced nigrostriatal degeneration. This suggests possible new therapeutic targets for Parkinson Disease.

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“…Therefore, additional control experiments were performed by measurements in positive-ion mode. Tyrosine, which is structurally similar to DA but does not affect AS fibrillation 13 24,48 . Furthermore, Tyr binding does not induce changes in the CSD comparable to those observed with DA ( Fig.…”

Section: Da Binding Is Observed Preferentially With As In Partially Ementioning

confidence: 99%

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

et al. 2016

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The intrinsically disordered and amyloidogenic protein -synuclein (AS) has been linked to several neurodegenerative states, including Parkinson's disease. Here, nano-electrospray-ionization mass spectrometry (nano-ESI-MS), ion mobility (IM), and native top-down electron transfer dissociation (ETD) techniques are employed to study AS interaction with small molecules known to modulate its aggregation, such as epigallocatechin-3-gallate (EGCG) and dopamine (DA). The complexes formed by the two ligands under identical conditions reveal peculiar differences. While EGCG engages AS in compact conformations, DA preferentially binds to the protein in partially extended conformations. The two ligands also have different effects on AS structure as assessed by IM, with EGCG leading to protein compaction and DA to its extension. Native top-down ETD on the protein-ligand complexes shows how the different observed modes of binding of the two ligands could be related to their known opposite effects on AS aggregation. The results also show that the protein can bind either ligand in the absence of any covalent modifications, such as e.g. oxidation.

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Dopamine promotes α‐synuclein aggregation into SDS‐resistant soluble oligomers via a distinct folding pathway

Cited by 246 publications

References 46 publications

Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking

Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking

The phosphorylation state of Ser-129 in human α-synuclein determines neurodegeneration in a rat model of Parkinson disease

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

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