A proposed dual role of neuromelanin in the pathogenesis of Parkinson’s disease

Zecca, Luigi; Zucca, Fabio A.; Albertini, Alberto; Rizzio, E.; Fariello, Ruggero G.

doi:10.1212/wnl.67.7_suppl_2.s8

Cited by 101 publications

(83 citation statements)

References 43 publications

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“…Moreover, the loss of neuromelanin observed in Parkinson's disease is accompanied by an increase in iron levels in the brain. In agreement with those considerations, a dual role for neuromelanin in the pathogenesis of that disease has been proposed [184]. On the other hand, neuromelanin should been considered as a neuroprotective agent, but it is also a molecule which accumulates a variety of potentially damaging species and also drugs such as amphetamines [185] and MPTP [186], so that this accumulation in the brain can also become a thread for neurodegeneration.…”

Section: Melanin Functionsmentioning

confidence: 88%

Melanins: Skin Pigments and Much More—Types, Structural Models, Biological Functions, and Formation Routes

Solano

2014

New Journal of Science

429

431

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This review presents a general view of all types of melanin in all types of organisms. Melanin is frequently considered just an animal cutaneous pigment and is treated separately from similar fungal or bacterial pigments. Similarities concerning the phenol precursors and common patterns in the formation routes are discussed. All melanins are formed in a first enzymatically-controlled phase, generally a phenolase, and a second phase characterized by an uncontrolled polymerization of the oxidized intermediates. In that second phase, quinones derived from phenol oxidation play a crucial role. Concerning functions, all melanins show a common feature, a protective role, but they are not merely photoprotective pigments against UV sunlight. In pathogenic microorganisms, melanization becomes a virulence factor since melanin protects microbial cells from defense mechanisms in the infected host. In turn, some melanins are formed in tissues where sunlight radiation is not a potential threat. Then, their redox, metal chelating, or free radical scavenging properties are more important than light absorption capacity. These pigments sometimes behave as a doubleedged sword, and inhibition of melanogenesis is desirable in different cells. Melanin biochemistry is an active field of research from dermatological, biomedical, cosmetical, and microbiological points of view, as well as fruit technology.

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Section: Melanin Functionsmentioning

confidence: 88%

Melanins: Skin Pigments and Much More—Types, Structural Models, Biological Functions, and Formation Routes

Solano

2014

New Journal of Science

429

431

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“…Additionally, neuromelanin is generally regarded as a powerful antioxidant [64]. However, neuromelanin may become deleterious in Parkinson disease as the disease progresses [65]. If 5-S-L-cysteinyldopamine were an aminotransferase/ oxidase substrate in vivo then formation of the α-keto acid might be a regulatory factor in the formation of neuromelanin and an additional detoxification mechanism.…”

Section: Discussionmentioning

confidence: 99%

Substrate specificity of human glutamine transaminase K as an aminotransferase and as a cysteine S-conjugate β-lyase

Cooper

Pinto

Krasnikov

et al. 2008

Archives of Biochemistry and Biophysics

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Rat kidney glutamine transaminase K (GTK) exhibits broad specificity both as an aminotransferase and as a cysteine S-conjugate β-lyase. The β-lyase reaction products are pyruvate, ammonium and a sulfhydryl-containing fragment. We show here that recombinant human GTK (rhGTK) also exhibits broad specificity both as an aminotransferase and as a cysteine S-conjugate β-lyase. S-(1,1,2,2-Tetrafluoroethyl)-L-cysteine is an excellent aminotransferase and β-lyase substrate of rhGTK. Moderate aminotransferase and β-lyase activities occur with the chemopreventive agent Se-methyl-L-selenocysteine. L-3-(2-Naphthyl)alanine, L-3-(1-naphthyl)alanine, 5-S-L-cysteinyldopamine and 5-S-L-cysteinyl-L-DOPA are measurable aminotransferase substrates, indicating that the active site can accommodate large aromatic amino acids. The α-keto acids generated by transamination/Lamino acid oxidase activity of the two catechol cysteine S-conjugates are unstable. A slow rhGTKcatalyzed β-elimination reaction, as measured by pyruvate formation, was demonstrated with 5-S-L-cysteinyldopamine, but not with 5-S-L-cysteinyl-L-DOPA. The importance of transamination, oxidation and β-elimination reactions involving 5-S-L-cysteinyldopamine, 5-S-L-cysteinyl-L-DOPA and Se-methyl-L-selenocysteine in human tissues and their biological relevance are discussed. KeywordsCysteine S-conjugate β-lyase; 5-S-L-cysteinyl-L-DOPA; 5-S-L-cysteinyldopamine; glutamine transaminase K; Se-methyl-L-selenocysteine Glutamine transaminase K (GTK) 1 purified from rat and bovine tissues accepts a large number of neutral, aromatic and sulfur/selenium-containing substrates [1][2][3][4][5][6]. GTK catalyzes *Corresponding author: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA. Fax: +1 914 594 4058, E-mail address: arthur_cooper@nymc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 Abbreviations used: BTC, benzothiazolyl-L-cysteine; DCVC, S-(1,2-dichlorovinyl)-L-cysteine; DOPA, dihydroxyphenylalanine; DTNB, 5,5′-dithiobis(2-nitrobenzoic acid); DTT, dithiothreitol; GSH, glutathione; KAT, kynurenine aminotransferase; KGDHC, α-ketoglutarate dehydrogenase complex; KGM, α-ketoglutaramate; KMB, α-keto-γ-methiolbutyrate; MBTH, 3-methyl-2-benzothiazolinone hydrazone; MDH, malate dehydrogenase; MPA, metaphosphoric acid; PDHC, pyruvate dehydrogenase complex; PLP, pyridoxal 5′-phosphate; rhGTK, recombinant human glutamine transaminase K; TFEC, S- (1,1,2,2-tetrafluoroethyl) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript transamination of kynurenine to kynurenate, ...

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“…There is evidence to suggest that neuromelanin acts to reduce potentially toxic iron by chelating iron found in the cytosol of neurons. 59,60 The CSF and brain interstitium probably also contain unbound extracellular iron, which is likely complexed with citrate and taken into cells through a nontransferrin receptor-mediated mechanism. 61 Finally, after the brain uses the iron it has stored, the iron must leave the cell, and the copper-associated protein ceruloplasmin may facilitate cellular release of iron.…”

Section: Iron Transportmentioning

confidence: 99%

“…6 Additionally, iron-associated proteins and receptors are upregulated in the striatum and substantia nigra of patients with PD. 60,94 Increased iron levels are thought to produce free radicals and predispose dopamine striatonigral neurons to oxidative damage. 60,94 -96 Oxidative stress compromises lipid, protein, and DNA molecular integrity, leading to neuronal injury.…”

Section: Parkinson's Diseasementioning

confidence: 99%

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

et al. 2007

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Summary:Iron is important for brain oxygen transport, electron transfer, neurotransmitter synthesis, and myelin production. Though iron deposition has been observed in the brain with normal aging, increased iron has also been shown in many chronic neurological disorders including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. In vitro studies have demonstrated that excessive iron can lead to free radical production, which can promote neurotoxicity. However, the link between observed iron deposition and pathological processes underlying various diseases of the brain is not well understood. It is not known whether excessive in vivo iron directly contributes to tissue damage or is solely an epiphenomenon. In this article, we focus on the imaging of brain iron and the underlying physiology and metabolism relating to iron deposition. We conclude with a discussion of the potential implications of iron-related toxicity to neurotherapeutic development.

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A proposed dual role of neuromelanin in the pathogenesis of Parkinson’s disease

Cited by 101 publications

References 43 publications

Melanins: Skin Pigments and Much More—Types, Structural Models, Biological Functions, and Formation Routes

Melanins: Skin Pigments and Much More—Types, Structural Models, Biological Functions, and Formation Routes

Substrate specificity of human glutamine transaminase K as an aminotransferase and as a cysteine S-conjugate β-lyase

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

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