DT-Diaphorase Prevents Aminochrome-Induced Alpha-Synuclein Oligomer Formation and Neurotoxicity

Muñoz, Patricia; Cárdenas, Sergio; Huenchuguala, Sandro; Briceño, Andrea; Couve, Eduardo; Paris, Irmgard; Segura‐Aguilar, Juan

doi:10.1093/toxsci/kfv016

Cited by 67 publications

(52 citation statements)

References 43 publications

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“…Aminochrome interacts with human α-synuclein, inducing and stabilizing the formation of neurotoxic oligomers (Muñoz et al, 2015; Norris et al, 2005). Recently, by using a rat cell line with stable over-expression of wild type α-synuclein and a siRNA against the DT-diaphorase enzyme, it has been demonstrated that the neurotoxicity of α-synuclein oligomers depends on the silencing of DT-diaphorase enzyme (Muñoz et al, 2015).…”

Section: Iron In Da Oxidationmentioning

confidence: 99%

“…Recently, by using a rat cell line with stable over-expression of wild type α-synuclein and a siRNA against the DT-diaphorase enzyme, it has been demonstrated that the neurotoxicity of α-synuclein oligomers depends on the silencing of DT-diaphorase enzyme (Muñoz et al, 2015). This enzyme is a flavoenzyme that catalyzes the two-electron reduction of aminochrome to leukoaminochrome, thus preventing the formation of neurotoxic α-synuclein oligomers induced by aminochrome.…”

Section: Iron In Da Oxidationmentioning

confidence: 99%

“…This enzyme is a flavoenzyme that catalyzes the two-electron reduction of aminochrome to leukoaminochrome, thus preventing the formation of neurotoxic α-synuclein oligomers induced by aminochrome. Interestingly, DT-diaphorase prevents α-synuclein fibrillation, probably because leukoaminochrome can stabilize α-synuclein in the monomer state (Muñoz et al, 2015). …”

Section: Iron In Da Oxidationmentioning

confidence: 99%

“…Interestingly, the products of DA oxidation (DA- o -quinone, aminochrome and 5,6-indolequinone) are directly involved in mitochondria dysfunction, protein degradation alteration, α-synuclein aggregation to neurotoxic oligomers and oxidative stress in dopaminergic neurons (Fig. 1, 2), suggesting that these o -quinones can play an important role in the degenerative process, resulting in the loss of SN dopaminergic neurons containing NM (Aguirre et al, 2012; Arriagada et al, 2004; Bisaglia et al, 2007; Dibenedetto et al, 2013; Hauser and Hastings, 2013; Huenchuguala et al, 2014; LaVoie et al, 2005; Martinez-Vicente et al, 2008; Muñoz et al, 2012a, 2015; Norris et al, 2005; Paris et al, 2010; Van Laar et al, 2009; Whitehead et al, 2001; Xiong et al, 2014; Xu et al, 1998; Zafar et al, 2006; Zhou and Lim, 2009). …”

Section: Role Of Da Oxidation In Neurodegenerative Processes Of Pdmentioning

confidence: 99%

“…1, 2). The neurotoxic reactions in which aminochrome is involved are: i) α-synuclein aggregation to neurotoxic oligomers both in vitro and in cell line experiments (Dibenedetto et al, 2013; Muñoz et al, 2015; Norris et al, 2005); ii) protein degradation dysfunction that includes proteasome system impairment in different in vitro models (Xiong et al, 2014; Zafar et al, 2006; Zhou and Lim, 2009), inhibition of the fusion of autophagic vacuoles with lysosomes (Huenchuguala et al, 2014; Muñoz et al, 2012a; Paris et al, 2010), and lysosomal dysfunction (Huenchuguala et al, 2014) in rat and human cell lines; iii) oxidative stress with the formation of hydroxyl radicals during one-electron reduction of aminochrome to leukoaminochrome- o -semiquinone radical, which is extremely unstable in the presence of oxygen in a rat cell line (Arriagada et al, 2004); iv) mitochondrial dysfunction by inhibiting complex I of electron transport chain with a significant decrease in ATP in SH-SY5Y cells (Aguirre et al, 2012). …”

Section: Role Of Da Oxidation In Neurodegenerative Processes Of Pdmentioning

confidence: 99%

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Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease

Zucca

Segura‐Aguilar

Ferrari

et al. 2017

Progress in Neurobiology

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482

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There are several interrelated mechanisms involving iron, dopamine, and neuromelanin in neurons. Neuromelanin accumulates during aging and is the catecholamine-derived pigment of the dopamine neurons of the substantia nigra and norepinephrine neurons of the locus coeruleus, the two neuronal populations most targeted in Parkinson’s disease. Many cellular redox reactions rely on iron, however an altered distribution of reactive iron is cytotoxic. In fact, increased levels of iron in the brain of Parkinson’s disease patients are present. Dopamine accumulation can induce neuronal death; however, excess dopamine can be removed by converting it into a stable compound like neuromelanin, and this process rescues the cell. Interestingly, the main iron compound in dopamine and norepinephrine neurons is the neuromelanin-iron complex, since neuromelanin is an effective metal chelator. Neuromelanin serves to trap iron and provide neuronal protection from oxidative stress. This equilibrium between iron, dopamine, and neuromelanin is crucial for cell homeostasis and in some cellular circumstances can be disrupted. Indeed, when neuromelanin-containing organelles accumulate high load of toxins and iron during aging a neurodegenerative process can be triggered. In addition, neuromelanin released by degenerating neurons activates microglia and the latter cause neurons death with further release of neuromelanin, then starting a self-propelling mechanism of neuroinflammation and neurodegeneration. Considering the above issues, age-related accumulation of neuromelanin in dopamine neurons shows an interesting link between aging and neurodegeneration.

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Section: Iron In Da Oxidationmentioning

confidence: 99%

Section: Iron In Da Oxidationmentioning

confidence: 99%

Section: Iron In Da Oxidationmentioning

confidence: 99%

Section: Role Of Da Oxidation In Neurodegenerative Processes Of Pdmentioning

confidence: 99%

Section: Role Of Da Oxidation In Neurodegenerative Processes Of Pdmentioning

confidence: 99%

See 3 more Smart Citations

Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease

Zucca

Segura‐Aguilar

Ferrari

et al. 2017

Progress in Neurobiology

Self Cite

546

482

View full text Add to dashboard Cite

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Dopamin, oxidativer Stress und Protein‐Chinonmodifikationen bei Parkinson und anderen neurodegenerativen Erkrankungen

Monzani¹,

Nicolis²,

Dell’Acqua³

et al. 2019

Angewandte Chemie

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Dopamin (DA) ist das wichtigste und häufigste Catecholamin im Gehirn und zugleich Vorläufer anderer Neurotransmitter. Die Degeneration von Neuronen des Nigrostriatums (Substantia nigra, Pars compacta) bei Parkinson‐Kranken ist die am besten untersuchte Verknüpfung zwischen Neurotransmission und Neuropathologie durch DA. Catecholamine sind reaktive Moleküle, für die es komplexe Kontroll‐ und Transportsysteme gibt. Unter normalen Bedingungen werden kleine Mengen cytosolischen Dopamins unter Melanisierung von Peptiden und Proteinen schrittweise zu Neuromelanin umgewandelt. Überschießendes cytosolisches oder extraneuronales DA kann allerdings unselektive Proteinmodifikationen auslösen. Die dabei ablaufende Oxidation von DA zu Chinonverbindungen hängt von der Gegenwart redoxaktiver Übergangsmetallionen wie Eisen und Kupfer ab. Auch andere oxidierte DA‐Metaboliten sind wahrscheinlich an posttranslationalen Proteinmodifikationen beteiligt. Die Protein‐Chinonmodifikation ist also ein heterogener Vorgang mit verschiedenen DA‐Abkömmlingen, die Struktur‐ und Konformationsänderungen von Proteinen hervorrufen; dies kann zur Aggregation und Inaktivierung der modifizierten Proteine führen.

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Dopamine, Oxidative Stress and Protein–Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases

et al. 2019

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Dopamine (DA) is the most important catecholamine in the brain, as it is the most abundant and the precursor of other neurotransmitters. Degeneration of nigrostriatal neurons of substantia nigra pars compacta in Parkinson's disease represents the best‐studied link between DA neurotransmission and neuropathology. Catecholamines are reactive molecules that are handled through complex control and transport systems. Under normal conditions, small amounts of cytosolic DA are converted to neuromelanin in a stepwise process involving melanization of peptides and proteins. However, excessive cytosolic or extraneuronal DA can give rise to nonselective protein modifications. These reactions involve DA oxidation to quinone species and depend on the presence of redox‐active transition metal ions such as iron and copper. Other oxidized DA metabolites likely participate in post‐translational protein modification. Thus, protein–quinone modification is a heterogeneous process involving multiple DA‐derived residues that produce structural and conformational changes of proteins and can lead to aggregation and inactivation of the modified proteins.

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DT-Diaphorase Prevents Aminochrome-Induced Alpha-Synuclein Oligomer Formation and Neurotoxicity

Cited by 67 publications

References 43 publications

Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease

Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease

Dopamin, oxidativer Stress und Protein‐Chinonmodifikationen bei Parkinson und anderen neurodegenerativen Erkrankungen

Dopamine, Oxidative Stress and Protein–Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases

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