On the Role of Aminochrome in Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Parkinson's Disease

Segura‐Aguilar, Juan

doi:10.3389/fnins.2019.00271

Cited by 34 publications

(18 citation statements)

References 65 publications

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“…It has long been suspected that DA oxidation products contribute to the pathogenesis of PD (Blaschko, 1952;Carlsson and Fornstedt, 1991;Mattammal et al, 1995;Burbulla et al, 2017), and in particular interact with AS to challenge dopaminergic neuronal homeostasis (Mazzulli et al, 2007;Goldstein et al, 2014;Mor et al, 2017Mor et al, , 2019. There are two general routes by which this could happen: 1) nonenzymatic oxidation of DA to DA-Q, with subsequent formation of DA-Q-derived compounds such as aminochrome (Linsenbardt et al, 2012;Segura-Aguilar, 2019), isoquinolines (Storch et al, 2002), and 5-S-cysteinyldopamine (Montine et al, 1997;Badillo-Ramírez et al, 2019); and 2) MAO-catalyzed enzymatic oxidation of DA to form DOPAL (Mattammal et al, 1995), with spontaneous oxidation of DOPAL to DOPAL-quinone (DOPAL-Q) (Anderson et al, 2011;Follmer et al, 2015;Jinsmaa et al, 2018) (see the Visual Abstract). These two routes have been studied almost completely separately by different research groups.…”

Section: Discussionmentioning

confidence: 99%

“…An almost completely independent line of research has centered on potentially harmful effects of spontaneous oxidation of DA (Hastings, 2009;Surmeier et al, 2011;Burbulla et al, 2017;Herrera et al, 2017). DA can undergo oxidation to form dopamine-quinone (DA-Q) and then a variety of potentially neurotoxic compounds such as aminochrome (Linsenbardt et al, 2009;Paris et al, 2009;Segura-Aguilar, 2019), 5-S-cysteinyldopamine (Montine et al, 1997;Badillo-Ramírez et al, 2019), and isoquinolines (Nagatsu, 1997;Storch et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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3,4-Dihydroxyphenylacetaldehyde Is More Efficient than Dopamine in Oligomerizing and Quinonizing α-Synuclein

Jinsmaa

Isonaka

Sharabi

et al. 2019

J Pharmacol Exp Ther

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Lewy body diseases such as Parkinson's disease involve intraneuronal deposition of the protein a-synuclein (AS) and depletion of nigrostriatal dopamine (DA). Interactions of AS with DA oxidation products may link these neurohistopathologic and neurochemical abnormalities via two potential pathways: spontaneous oxidation of DA to dopamine-quinone and enzymatic oxidation of DA catalyzed by monoamine oxidase to form 3,4dihydroxyphenylacetaldehyde (DOPAL), which is then oxidized to DOPAL-Q. We compared these two pathways in terms of the ability of DA and DOPAL to modify AS. DOPAL was far more potent than DA both in oligomerizing and forming quinoneprotein adducts with (quinonizing) AS. The DOPAL-induced protein modifications were enhanced similarly by pro-oxidation with Cu(II) or tyrosinase and inhibited similarly by antioxidation with N-acetylcysteine. Dopamine oxidation evoked by Cu(II) or tyrosinase did not quinonize AS. In cultured MO3.13 human oligodendrocytes DOPAL resulted in the formation of numerous intracellular quinoproteins that were visualized by near-infrared spectroscopy. We conclude that of the two routes by which oxidation of DA modifies AS and other proteins the route via DOPAL is more prominent. The results support developing experimental therapeutic strategies that might mitigate deleterious modifications of proteins such as AS in Lewy body diseases by targeting DOPAL formation and oxidation. SIGNIFICANCE STATEMENT Interactions of the protein a-synuclein with products of dopamine oxidation in the neuronal cytoplasm may link two hallmark abnormalities of Parkinson disease: Lewy bodies (which contain abundant AS) and nigrostriatal DA depletion (which produces the characteristic movement disorder). Of the two potential routes by which DA oxidation may alter AS and other proteins, the route via the autotoxic catecholaldehyde 3,4-dihydroxyphenylacetaldehyde is more prominent; the results support experimental therapeutic strategies targeting DOPAL formation and DOPALinduced protein modifications.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

3,4-Dihydroxyphenylacetaldehyde Is More Efficient than Dopamine in Oligomerizing and Quinonizing α-Synuclein

Jinsmaa

Isonaka

Sharabi

et al. 2019

J Pharmacol Exp Ther

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“…Aminochrome is a substrate for NQO1 [ 101 ] and despite generating a redox labile hydroquinone [ 99 , 101 , 102 ], NQO1 protects against many of the toxic effects induced by aminochrome. In dopaminergic cells, NQO1 has been found to be protective against aminochrome induced adverse effects including mitochondrial damage and ER stress [ 103 ], alpha synuclein oligomer formation [ 104 ], proteasomal dysfunction [ 99 ], lysosome dysfunction [ 105 ], microtubule and cytoskeletal damage [ 106 , 107 ] and autophagy [ 108 ]. NQO1 also protects dopaminergic cells against dopamine [ 109 ] and aminochrome induced cell death [ 110 ].…”

Section: Are There Endogenous Quinone Substrates For Nqo1?mentioning

confidence: 99%

The diverse functionality of NQO1 and its roles in redox control

2021

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In this review, we summarize the multiple functions of NQO1, its established roles in redox processes and potential roles in redox control that are currently emerging. NQO1 has attracted interest due to its roles in cell defense and marked inducibility during cellular stress. Exogenous substrates for NQO1 include many xenobiotic quinones. Since NQO1 is highly expressed in many solid tumors, including via upregulation of Nrf2, the design of compounds activated by NQO1 and NQO1-targeted drug delivery have been active areas of research. Endogenous substrates have also been proposed and of relevance to redox stress are ubiquinone and vitamin E quinone, components of the plasma membrane redox system. Established roles for NQO1 include a superoxide reductase activity, NAD + generation, interaction with proteins and their stabilization against proteasomal degradation, binding and regulation of mRNA translation and binding to microtubules including the mitotic spindles. We also summarize potential roles for NQO1 in regulation of glucose and insulin metabolism with relevance to diabetes and the metabolic syndrome, in Alzheimer's disease and in aging. The conformation and molecular interactions of NQO1 can be modulated by changes in the pyridine nucleotide redox balance suggesting that NQO1 may function as a redox-dependent molecular switch.

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“…This spurred a line of research implicating dopamine itself as an autotoxin, based on oxidation of dopamine to dopamine-quinone and then a variety of distal oxidation products [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ] ( Figure 1 and Figure 2 ). Some of these are known to be neurotoxic, such as aminochrome [ 47 , 67 , 68 ], Cys-DA [ 66 , 69 ], and isoquinolines [ 70 , 71 ]. These products of spontaneous dopamine oxidation have in common that they are toxic to mitochondria [ 54 ].…”

Section: Toxicity From Spontaneous Oxidation Of Cytoplasmic Dopaminementioning

confidence: 99%

The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know

Goldstein

2021

IJMS

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3,4-Dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson’s disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally, DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (αS), a major component of Lewy bodies. DOPAL potently oligomerizes αS, and αS oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward the MAO-catalyzed formation of DOPAL—destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could “freeze” intraneuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with αS, and vice versa, is poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intraneuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.

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On the Role of Aminochrome in Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Parkinson's Disease

Cited by 34 publications

References 65 publications

3,4-Dihydroxyphenylacetaldehyde Is More Efficient than Dopamine in Oligomerizing and Quinonizing α-Synuclein

3,4-Dihydroxyphenylacetaldehyde Is More Efficient than Dopamine in Oligomerizing and Quinonizing α-Synuclein

The diverse functionality of NQO1 and its roles in redox control

The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know

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