In vitro neurotoxicity of salsolinol is attenuated by the presynaptic protein α-synuclein

Carmo-Gonçalves, Phelippe; Coelho-Cerqueira, Eduardo; Cortines, Juliana R.; Souza, Theo Luiz Ferraz de; Romão, Luciana; Follmer, Cristian

doi:10.1016/j.bbagen.2018.08.022

Cited by 6 publications

(12 citation statements)

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“…SALSO, a product of the reaction of DA with acetaldehyde formed via either Pictet–Spengler reaction or enzymatically by action of salsolinol synthase, is found significantly increased in cerebrospinal fluid and urine of PD patients under levodopa therapy. , SALSO induces an increase of oxidative stress and inhibition of mitochondrial function that can elicit dopaminergic cell death. , Intraperitoneal administration of SALSO in rats resulted in degeneration of myenteric neurons accompanied by the formation of aSyn inclusions . Interestingly, recent data from our group suggested a possible protective role of aSyn monomer against SALSO-induced toxicity in mesencephalic neurons in primary culture . DOPAL, a cytotoxic aldehyde produced from the enzymatic oxidation of DA by action of monoamine oxidase (MAO), is found to be enhanced in postmortem brains of PD patients .…”

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confidence: 76%

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In Vitro Protective Action of Monomeric and Fibrillar α-Synuclein on Neuronal Cells Exposed to the Dopaminergic Toxins Salsolinol and DOPAL

Carmo-Gonçalves

Romão

Follmer

2020

ACS Chem. Neurosci.

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The aggregation of α-synuclein (aSyn) is believed to be mechanistically linked to the degeneration of dopamine (DA)-producing neurons in Parkinson’s disease (PD). In this respect, one crucial question that yet remains unsolved is whether aSyn aggregation is associated with either a gain- or loss-of-function of the protein in neuronal cells. Herein, we investigated the effect of monomeric versus fibrillar aSyn on mesencephalic dopaminergic neurons in primary cultures challenged with the neurotoxic catechols: salsolinol (SALSO; 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) and 3,4-dihydroxyphenylacetaldehyde (DOPAL). aSyn monomer protected cells against either SALSO- or DOPAL-induced toxicity via inhibition of caspase-3-mediated apoptosis. While fibrillar aSyn failed in attenuating SALSO neurotoxicity, it increased the viability of DOPAL-treated cells, which was apparently not associated with the inhibition of caspase-3 cleavage. The fact that DOPAL-derived aSyn adducts exhibit lower toxicity compared with DOPAL itself raises the question of whether the generation of these adducts could be part of or a collateral effect of aSyn-mediated protection in neurons exposed to DOPAL. Overall, our work provides important evidence on the impact of the fibrillation of aSyn on its protective role in neuronal cells exposed to the toxic catechols SALSO and DOPAL.

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confidence: 76%

“…Considering our previous data showing that aSyn monomer is able to attenuate the toxicity promoted by SALSO in neuronal cells, 13 we decided to evaluate the effect of the formation of fibrils on the neuroprotective role of the protein.…”

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confidence: 99%

In Vitro Protective Action of Monomeric and Fibrillar α-Synuclein on Neuronal Cells Exposed to the Dopaminergic Toxins Salsolinol and DOPAL

Carmo-Gonçalves

Romão

Follmer

2020

ACS Chem. Neurosci.

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“…Our protocol for preparation of mesDA neurons culture yields more than 85% of cultured neurons positive for tyrosine hydroxylase [23]. The methodology based on exogenous addition of aSyn is supported by previous studies that indicate that aSyn aggregates (fibrils or oligomers) can enter cells when added to cultured neurons [21,22,[26][27][28][29], where they generate toxic effects associated with neurodegeneration, such as apoptosis and synaptic dysfunction. MesDA cells treated for 24 h with aSyn alone (final concentration of 20 µM in relation to monomer) display a viability similar to that of the control, whereas diminished cell viability is observed when the protein is in the presence of increasing concentrations of Apo (Fig.…”

Section: Apo Induces the Formation Of Toxic Asyn Oligomersmentioning

confidence: 66%

“…Isolation, culture, and maintenance of primary culture of mesDA neurons from the midbrain of 14-day-old Swiss mice (E14) were done as previously described [21][22][23]. All animals were kept under standard laboratory conditions according to National Institute of Health guidelines and using the protocols approved by the Animal Use Ethics Committee of the Federal University of Rio de Janeiro (Protocol No 025/15).…”

Section: Toxicity Assaysmentioning

confidence: 99%

The dopamine receptor agonist apomorphine stabilizes neurotoxic α‐synuclein oligomers

et al. 2021

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The misfolding and aggregation of the protein α-synuclein (aSyn) into potentially neurotoxic oligomers is believed to play a pivotal role in the neuropathogenesis of Parkinson's disease (PD). Herein, we explore how apomorphine (Apo), a nonselective dopamine D1 and D2 receptor agonist utilized in the therapy for PD, affects the aggregation and toxicity of aSyn in vitro. Our data indicated that Apo inhibits aSyn fibrillation leading to the formation of large oligomeric species (Apo-aSyn-O), which exhibit remarkable toxicity in mesencephalic dopaminergic neurons in primary cultures. Interestingly, purified Apo-aSyn-O, even at very low concentrations, seems to be capable of converting unmodified aSyn monomer into neurotoxic species. Collectively, our findings warn for a possible dangerous effect of Apo on aSyn misfolding/aggregation pathway.

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“…Interestingly, β‐Syn has a much higher affinity for DOPAL and a much lower affinity for DA as compared to α‐Syn. It remains to be determined if further oxidized metabolites of DA such as dopamine‐o‐quinone (Asanuma et al., 2003), 5,6‐Dihydroxyindole (Pham et al., 2009), Indole‐5,6‐quinone (Bisaglia, Mammi, & Bubacco, 2007), or salsolinol (do Carmo‐Goncalves, 2018), are also interacting with β‐Syn and α‐Syn with significantly different affinities. If this would be the case, then not only the levels of oxidized metabolites of DA and of the synucleins may be important for the etiology of synucleinopathies, but also cellular conditions which favor generation of the one over the other metabolite of DA.…”

Section: Discussionmentioning

confidence: 99%

Dopamine promotes the neurodegenerative potential of β‐synuclein

Raina

Leite

Guerin

et al. 2020

Journal of Neurochemistry

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A contribution of α‐Synuclein (α‐Syn) to etiology of Parkinson´s disease (PD) and Dementia with Lewy bodies (DLB) is currently undisputed, while the impact of the closely related β‐Synuclein (β‐Syn) on these disorders remains enigmatic. β‐Syn has long been considered to be an attenuator of the neurotoxic effects of α‐Syn, but in a rodent model of PD β‐Syn induced robust neurodegeneration in dopaminergic neurons of the substantia nigra. Given that dopaminergic nigral neurons are selectively vulnerable to neurodegeneration in PD, we now investigated if dopamine can promote the neurodegenerative potential of β‐Syn. We show that in cultured rodent and human neurons a dopaminergic neurotransmitter phenotype substantially enhanced β‐Syn‐induced neurodegeneration, irrespective if dopamine is synthesized within neurons or up‐taken from extracellular space. Nuclear magnetic resonance interaction and thioflavin‐T incorporation studies demonstrated that dopamine and its oxidized metabolites 3,4‐dihydroxyphenylacetaldehyde (DOPAL) and dopaminochrome (DCH) directly interact with β‐Syn, thereby enabling structural and functional modifications. Interaction of DCH with β‐Syn inhibits its aggregation, which might result in increased levels of neurotoxic oligomeric β‐Syn. Since protection of outer mitochondrial membrane integrity prevented the additive neurodegenerative effect of dopamine and β‐Syn, such oligomers might act at a mitochondrial level similar to what is suggested for α‐Syn. In conclusion, our results suggest that β‐Syn can play a significant pathophysiological role in etiology of PD through its interaction with dopamine metabolites and thus should be re‐considered as a disease‐relevant factor, at least for those symptoms of PD that depend on degeneration of nigral dopaminergic neurons.

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In vitro neurotoxicity of salsolinol is attenuated by the presynaptic protein α-synuclein

Cited by 6 publications

References 58 publications

In Vitro Protective Action of Monomeric and Fibrillar α-Synuclein on Neuronal Cells Exposed to the Dopaminergic Toxins Salsolinol and DOPAL

In Vitro Protective Action of Monomeric and Fibrillar α-Synuclein on Neuronal Cells Exposed to the Dopaminergic Toxins Salsolinol and DOPAL

The dopamine receptor agonist apomorphine stabilizes neurotoxic α‐synuclein oligomers

Dopamine promotes the neurodegenerative potential of β‐synuclein

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