Increased dopamine peroxidation in postmortem Parkinsonian brain

Iuliis, Angela De; Boschetto, Roberta; Zambenedetti, Pamela; Arslan, Paola; Galzigna, L

doi:10.1016/s0304-4165(02)00331-8

Cited by 20 publications

(14 citation statements)

References 25 publications

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“…Dopaminochrome can be produced from dopamine through enzymatic oxidation or autoxidation. De Iuliis has demonstrated that PD brains have an increase in peroxidation activity postmortem (De Iuliis et al, 2002) which was supported by a previous study demonstrating that brain peroxidases can catalyze the formation of dopaminochrome (Galzigna et al, 1999b). This peroxidase activity may be attributed to prostaglandin H synthase as proposed by Hastings (1995).…”

Section: Discussionmentioning

confidence: 52%

The separation and quantification of aminochromes using high-pressure liquid chromatography with electrochemical detection

Ochs¹,

Westfall²,

Macarthur³

2005

Journal of Neuroscience Methods

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Section: Discussionmentioning

confidence: 52%

The separation and quantification of aminochromes using high-pressure liquid chromatography with electrochemical detection

Ochs¹,

Westfall²,

Macarthur³

2005

Journal of Neuroscience Methods

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“…However, a build-up of oxidized forms of DA-related compounds such as DA-quinones may drive the synthesis of neuromelanin from these compounds, a process that may compete with reduction of lipids (below) [21-23]. Depletion of glutathione and upregulation of GPX4 peroxidase activity in response to oxidative stress may further drive the production of neuromelanin and inhibit reduction of lipids [5]. Accumulated oxidized lipids are metabolized by 12/15-lipoxygenase, and metabolite products activate AIF to promote apoptotic cell death [16].…”

Section: Discussionmentioning

confidence: 99%

“…The formation is postulated to require hydroperoxidase activity. Peroxidase activity associated with neuromelanin has been demonstrated and is increased in postmortem PD brain [5]. However, a hydroperoxidase responsible for neuromelanin formation has not specifically been identified.…”

Section: Introductionmentioning

confidence: 99%

Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain

Bellinger

Seale

et al. 2011

Mol Neurodegeneration

131

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BackgroundParkinson's disease is a neurodegenerative disorder characterized pathologically by the loss of nigrostriatal dopamine neurons that project from the substantia nigra in the midbrain to the putamen and caudate nuclei, leading to the clinical features of bradykinesia, rigidity, and rest tremor. Oxidative stress from oxidized dopamine and related compounds may contribute to the degeneration characteristic of this disease.ResultsTo investigate a possible role of the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4) in protection from oxidative stress, we investigated GPX4 expression in postmortem human brain tissue from individuals with and without Parkinson's disease. In both control and Parkinson's samples, GPX4 was found in dopaminergic nigral neurons colocalized with neuromelanin. Overall GPX4 was significantly reduced in substantia nigra in Parkinson's vs. control subjects, but was increased relative to the cell density of surviving nigral cells. In putamen, GPX4 was concentrated within dystrophic dopaminergic axons in Parkinson's subjects, although overall levels of GPX4 were not significantly different compared to control putamen.ConclusionsThis study demonstrates an up-regulation of GPX4 in neurons of substantia nigra and association of this protein with dystrophic axons in striatum of Parkinson's brain, indicating a possible neuroprotective role. Additionally, our findings suggest this enzyme may contribute to the production of neuromelanin.

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“…In the mesencephalic cell line, MN9, aminochrome induces caspase-independent apoptosis (Linsenbardt et al, 2012). Aminochrome can also be formed from auto-oxidation of DA in the setting of hydrogen peroxide and a peroxidase, yielding a superoxide anion (Hastings, 1995), and activity of the peroxidase is increased in post-mortem midbrain tissue from PD patients (De Iuliis et al, 2002). …”

Section: Spontaneous Oxidation Of Catecholaminesmentioning

confidence: 99%

“…An alternative fate of hydrogen peroxide is reaction with the enzyme catalase to form water and oxygen. A peroxidase catalyzes formation of aminochrome from DA and hydrogen peroxide (De Iuliis et al, 2002), and activity of the peroxidase is increased in post-mortem midbrain tissue in PD.…”

Section: Monoamine Oxidase and The Enzymatic Oxidation Of Catecholmentioning

confidence: 99%

Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders

Goldstein

Kopin

Sharabi

2014

Pharmacology & Therapeutics

142

121

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Several neurodegenerative diseases involve loss of catecholamine neurons—Parkinson disease is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are vulnerable in PD and related disorders has been mysterious. Accumulating evidence supports the concept of “autotoxicity”—inherent cytotoxicity of catecholamines and their metabolites in the cells in which they are produced. According to the “catecholaldehyde hypothesis” for the pathogenesis of Parkinson disease, long-term increased build-up of 3,4-dihydroxyphenylacetaldehyde (DOPAL), the catecholaldehyde metabolite of dopamine, causes or contributes to the eventual death of dopaminergic neurons. Lewy bodies, a neuropathologic hallmark of PD, contain precipitated alpha-synuclein. Bases for the tendency of alpha-synuclein to precipitate in the cytoplasm of catecholaminergic neurons have also been mysterious. Since DOPAL potently oligomerizes and aggregates alpha-synuclein, the catecholaldehyde hypothesis provides a link between alpha-synucleinopathy and catecholamine neuron loss in Lewy body diseases. The concept developed here is that DOPAL and alpha-synuclein are nodes in a complex nexus of interacting homeostatic systems. Dysfunctions of several processes, including decreased vesicular sequestration of cytoplasmic catecholamines, decreased aldehyde dehydrogenase activity, and oligomerization of alpha-synuclein, lead to conversion from the stability afforded by negative feedback regulation to the instability, degeneration, and system failure caused by induction of positive feedback loops. These dysfunctions result from diverse combinations of genetic predispositions, environmental exposures, stress, and time. The notion of catecholamine autotoxicity has several implications for treatment, disease modification, and prevention. Conversely, disease modification clinical trials would provide key tests of the catecholaldehyde hypothesis.

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Increased dopamine peroxidation in postmortem Parkinsonian brain

Cited by 20 publications

References 25 publications

The separation and quantification of aminochromes using high-pressure liquid chromatography with electrochemical detection

The separation and quantification of aminochromes using high-pressure liquid chromatography with electrochemical detection

Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain

Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders

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