The chemical structural characterization of neuromelanins in human locus coeruleus and its aging process

• Project/Area Number: 15K09794
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Fujita Health University
• Principal Investigator: Wakamatsu Kazumasa 藤田保健衛生大学, 保健学研究科, 教授 (80131259)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ニューロメラニン / ドーパミン / pro-oxidant activity / ROS / antioxidant / GSH / ウシ血清アルブミン / β-ラクトグロブリン / pro-oxidant活性 / 過酸化水素 / カテコールアミン / 黒質 / BSA / DPRA / ノルエピネフリン / 青斑核

Outline of Final Research Achievements

Neuromelanin (NM), a dark brown pigment, is found in the Substantia Nigra (SN) in dopaminergic neurons and in the Locus coeruleus (LC) in norepinephrinergic neurons. This study shows that protein-bound dopamine (DA) conjugates formed during the production of NM have pro-oxidant activities that generate reactive oxygen species (ROS) and deplete reduced glutathione (GSH), the most important cellular antioxidant. Further, the results demonstrate that the DAquinone produced is bound to proteins via their SH groups and that the binding yield depends on the structural features of the protein. Binding via cysteine residues in proteins is formed by oxidation using redox-active metal ions as well as tyrosinase. These results suggest that protein-bound DA conjugates produced in the brain possess pro-oxidant activities, which may cause neurodegeneration due to the generation of ROS and the depletion of antioxidants.

Research Products

• [Int'l Joint Research] イタリア高等医科学研究所/Luigi Zecca(イタリア)
• [Int'l Joint Research] イタリア高等医科学研究所/Luigi Zecca(イタリア)
• [Journal Article] Insect cuticular melanins are distinctly different from those of mammalian epidermal melanins. (2018)
  • Author(s): Barek, H., Sugumaran, M., Ito, S., and Wakamatsu, K.
  • Journal Title: Pigment Cell Melanoma Res. Volume: 31 Issue: 3 Pages: 384-392
  • DOI: 10.1111/pcmr.12672
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Acid hydrolysis reveals a low but constant level of pheomelanin in human black to brown hair. (2018)
  • Author(s): Ito, S., Miyake, S., Maruyama, S., Suzuki, I., Commo, S., Nakanishi, Y., and Wakamatsu, K.
  • Journal Title: Pigment Cell Melanoma Res. Volume: 31 Issue: 3 Pages: 393-403
  • DOI: 10.1111/pcmr.12673
  • Peer Reviewed / Open Access
• [Journal Article] Pheomelanogenesis is Promoted at a Weakly Acidic pH. (2017)
  • Author(s): Wakamatsu, K., Nagao, A., Watanabe, M., Nakao, K., and Ito, S.
  • Journal Title: Pigment Cell Melanoma Res. Volume: 30 Issue: 3 Pages: 372-377
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  • Peer Reviewed / Open Access
• [Journal Article] CK1α ablation in keratinocytes induces p53-dependent, sunburn-protective, skin hyperpigmentation. (2017)
  • Author(s): Chang, C-H., Kuo, C-J., Ito, T., Su, Y-Y., Jiang, S-T., Chiou, M-H., Lin, Y-H., Nist, A., Mernberger, M., Stiewe, T., Ito, S., Wakamatsu, K., Alkalay, I., and Ben-Neriah, Y.
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 114 Issue: 38
  • DOI: 10.1073/pnas.1702763114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The potent pro-oxidant activity of rhododendrol-eumelanin induces cysteine depletion in B16 melanoma cells (2017)
  • Author(s): Ito, S., Okura, M., Wakamatsu, K., and Yamashita, T.
  • Journal Title: Pigment Cell Melanoma Res. Volume: 30 Issue: 1 Pages: 63-67
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  • Peer Reviewed / Open Access
• [Journal Article] The Tyrosinase-Catalyzed Oxidation of the Leukoderma-inducing Agent Raspberry Ketone Produces (E)-4-(3-oxo-1-butenyl)-1,2-benzoquinone. (2017)
  • Author(s): Ito, S., Hinoshita, M., Suzuki, E., Ojika, M., and Wakamatsu, K.
  • Journal Title: Chem. Res. Toxicol. Volume: 30 Issue: 3 Pages: 859-868
  • DOI: 10.1021/acs.chemrestox.7b00006
  • Peer Reviewed
• [Journal Article] MC1R variants affect the expression of melanocortin and melanogenic genes and the association between melanocortin genes and coloration. (2017)
  • Author(s): San-Jose, LM., Ducrest, A-L., Ducret, V., Simon, C., Richter, H., Wakamatsu, K., and Roulin, A.
  • Journal Title: Mol. Ecol. Volume: 26 Issue: 1 Pages: 259-276
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• [Journal Article] A novel locus on chromosome 1 underlies the evolution of a melanic plumage polymorphism in a wild songbird. (2017)
  • Author(s): Bourgeois, Y.X.C., Delahaie, B., Gautier, M., Lhuillier, E. Male, P-J.G., Bertrand, J.A.M., Cornuault, J., Wakamatsu, K., Bouchez, O., Mould, C., Bruxaux, J., Holota, H., Mila, B., Thebaud, C.
  • Journal Title: Royal Society Open Science Volume: - Issue: 2 Pages: 160805-160805
  • DOI: 10.1098/rsos.160805
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Physiological conditions and genetic controls of phaeomelanin pigmentation in nestling barn swallows. (2017)
  • Author(s): Arai, E., Hasegawa, M., Makino, T., Hagino, A., Sakai, Y., Otsuki, H., Wakamatsu, K., Kawata, M.
  • Journal Title: Behav. Ecol. Volume: 印刷中 Issue: 3 Pages: 706-716
  • DOI: 10.1093/beheco/arx012
  • Peer Reviewed
• [Journal Article] Rhododenol-induced leukoderma in a mouse model mimicking Japanese skin. (2016)
  • Author(s): Abe, Y., Okamura, K., Kawaguchi, M., Hozumi, Y., Aoki, H., Kunisada, T., Ito, S., Wakamatsu, K., Matsunaga, K., Suzuki, T.
  • Journal Title: J. Dermatol. Sci. Volume: 81 Issue: 1 Pages: 35-43
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  • Peer Reviewed
• [Journal Article] The Metabolic Fate of ortho-Quinones Derived from Catecholamine Metabolites. (2016)
  • Author(s): Ito, S., Yamanaka, Y., Ojika, M., Wakamatsu, K.
  • Journal Title: Int. J. Mol. Sci. Volume: 17 Issue: 2 Pages: 164-164
  • DOI: 10.3390/ijms17020164
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Circulating melanoma cells as a potential biomarker to detect metastasis and evaluate prognosis. (2016)
  • Author(s): Hida T, Yoneta A, Wakamatsu K, Yanagisawa K, Ishii-Osai Y, Kan Y, Kato J, Yamashita T
  • Journal Title: Australas J Dermatol. Volume: Mar Issue: 2 Pages: 145-149
  • DOI: 10.1111/ajd.12455
  • Peer Reviewed
• [Journal Article] Roles of reactive oxygen species in UVA-induced oxidation of 5,6-dihydroxyindole-2-carboxylic acid-melanin as studied by differential spectrophotometric method (2016)
  • Author(s): S Ito, M Kukita, S Koike, G Szewczyk, M Sarna, A Zadlo, T Sarna, K Wakamatsu
  • Journal Title: Pigment Cell Melanoma Res Volume: 29 Issue: 3 Pages: 340-351
  • DOI: 10.1111/pcmr.12469
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Quantifying variation in human scalp hair fiber shape and pigmentation (2016)
  • Author(s): T Lasisi, S Ito, K Wakamatsu, CN Shaw
  • Journal Title: Amer J Phys Anthropol Volume: 160 Issue: 2 Pages: 341-352
  • DOI: 10.1002/ajpa.22971
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of shell colour pigments in marine snails clanculus pharaonius and C. margaritarius (Trochoidea; Gastropoda). (2016)
  • Author(s): Williams, S.T., Ito, S., Wakamatsu, K., Goral, T., Edwards, N., Wogelius, R., Henkel, T., Oliveira, L.d., Maiai, L., Strekopytov, S., Jeffries, T. Speiser, D., Marsden, J.
  • Journal Title: Plos One Volume: 11 Issue: 7 Pages: e0156664-e0156664
  • DOI: 10.1371/journal.pone.0156664
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibitory effects of emodin on intestinal tumor development in Min mice. (2016)
  • Author(s): Shimpo, K., Chihara, T., Beppu, H., Kaneko, T., Shinzato, M., Wakamatsu, K., Higashiguchi, T., Sonoda, S.
  • Journal Title: Clinical Pharmacology and Therapy. Volume: 26 Pages: 45-54
  • Peer Reviewed
• [Journal Article] Scalp nevus depigmentosus with dermoscopy-detectable diverse hair color. (2016)
  • Author(s): Oiso, N., Wakamatsu, K., Kawada, A.
  • Journal Title: Eur. J. Dermatol. Volume: 26 Issue: 6 Pages: 622-623
  • DOI: 10.1684/ejd.2016.2859
  • Peer Reviewed
• [Journal Article] Color measurement of the animal integument predicts the content of specific melanin forms. (2016)
  • Author(s): Galvan, I., Wakamatsu, K.
  • Journal Title: RSC Advances. Volume: 6 Issue: 82 Pages: 79135-79142
  • DOI: 10.1039/c6ra17463a
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High brood patch temperature of less colourful, less pheomelanic female barn swallows hirundo rustica. (2016)
  • Author(s): Hasegawa, M., Arai, E., Ito, S., Wakamatsu, K.
  • Journal Title: Ibis Volume: 158 Pages: 808-820
  • Peer Reviewed
• [Journal Article] Aerobic photo reactivity of synthetic eumelanins and pheomelanins: generation of singlet oxygen and superoxide anion (2016)
  • Author(s): G Szewczyk, A Zadlo, M Sarna, S Ito, K Wakamatsu, T Sarna
  • Journal Title: Pigment Cell Melanoma Res Volume: 29 Issue: 6 Pages: 669-678
  • DOI: 10.1111/pcmr.12514
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Elemental characterization of melanin in feathers via synchrotron X-ray imaging and absorption spectroscopy (2016)
  • Author(s): NP Edwords, A van Veelen, J Anne, PL Manning, U Bergmann, WI Sellers, VM Egerton, D Sokoras, R, Anoso-Mori, K Wakamatsu, S Ito, RA Wogelius
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 1-10
  • DOI: 10.1038/srep34002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Norepinephrine and its metabolites are involved in the synthesis of neuromelanin derived from the locus coeruleus. (2015)
  • Author(s): Wakamatsu, K., Tabuchi, K., Ojika, M., Zucca, F. A., Zecca, L., Ito, S.
  • Journal Title: J. Neurochem. Volume: 135 Issue: 4 Pages: 768-776
  • DOI: 10.1111/jnc.13237
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] An insect with selective control of egg coloration. (2015)
  • Author(s): Abram, P. K., Guerra-Grenier, E., Després-Einspenner, M-L., Ito, S., Wakamatsu, K., Boivin, G., Brodeur, J.
  • Journal Title: Curr. Biol. Volume: 25 Issue: 15 Pages: 2007-2011
  • DOI: 10.1016/j.cub.2015.06.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Molecular composition and ultrastructure of Jurassic paravian feathers. (2015)
  • Author(s): Lindgren, J., Sjovall, P., Carney, R., Cincotta, A., Uvdal, P., Hutcheson, S., Gustafsson, O., Lefevre, U., Escuillie, F., Heimdal, J., Engdahl, A., Gren, J., Kear, B., Wakamatsu, K., Yans, J., Godefroit, P.
  • Journal Title: Sci. Rep. Volume: 5 Issue: 1 Pages: 13520-13520
  • DOI: 10.1038/srep13520
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chemiexcitation of Melanin Derivatives Induces DNA Photoproducts Long after UV exposure. (2015)
  • Author(s): Premi, S., Wallisch, S., Mano, C. M., Weiner, A. B., Bacchiocchi, A., Wakamatsu, K., Bechara, E. J. H., Halaban, R., Douki, T., Brash, D. E.
  • Journal Title: Science Volume: 347 Issue: 6224 Pages: 842-847
  • DOI: 10.1126/science.1256022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A convenient screening method to differentiate phenolic skin whitening tyrosinase inhibitors from leukoderma-inducing phenols. (2015)
  • Author(s): Ito, S., Wakamatsu, K.
  • Journal Title: J. Dermatol. Sci. Volume: 80 Issue: 1 Pages: 18-24
  • DOI: 10.1016/j.jdermsci.2015.07.007
  • Peer Reviewed
• [Journal Article] Tyrosinase-catalyzed metabolism of rhododendron (RD) in B16 melanoma cells: production of RD-pheomelanin and covalent binding with thiol proteins (2015)
  • Author(s): S Ito, M Okura, Y Nakanishi, M Ojika, K Wakamatsu, T Yamashita
  • Journal Title: Pigment Cell Melanoma Res Volume: 28 Issue: 3 Pages: 296-307
  • DOI: 10.1111/pcmr.12363
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effect of the MC1R gene on sexual dimorphism in melanin-based colorations. (2015)
  • Author(s): San-Jose, L. M., Ducrest, A-L., Ducret, V., Beziers, P., Simon, C., Wakamatsu, K., Roulin, A.
  • Journal Title: Mol. Ecol. Volume: 24 Pages: 2794-2808
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The slaty (slt/Dctslt) allele decreases the content of eumelanin, pheomelanin in the mouse hair. (2015)
  • Author(s): Hirobe, T., Ito, S., Wakamatsu, K.
  • Journal Title: Pigment Cell Melanoma Res. Volume: 29 Issue: 1 Pages: 110-112
  • DOI: 10.1111/pcmr.12427
  • Peer Reviewed
• [Presentation] Roles of pH in mixed melanogenesis. (2017)
  • Author(s): Wakamatsu, K
  • Organizer: 23rd International Pigment Cell Conference
  • Int'l Joint Research
• [Presentation] Structural modification in oxidative coupling reaction of dopamine to cysteine-containing peptidic moieties (2017)
  • Author(s): Nakao, K., Kumura, Y., Ojika, M., Ito, S., Wakamatsu, K
  • Organizer: 23rd International Pigment Cell Conference
  • Int'l Joint Research
• [Presentation] Pro-oxidant activity of mouse hair pheomelanin is promoted by UVA irradiation (2017)
  • Author(s): Tanaka, H., Yamashita, Y., Ito, S., Wakamatsu, K
  • Organizer: 23rd International Pigment Cell Conference
  • Int'l Joint Research
• [Presentation] Melanin analysis for hair samples from Japanese patients with Hermansky-Pudlak Syndrome type 1, 4, 6, and 9 (2017)
  • Author(s): Okamura, K., Araki, Y., Abe, Y., Wakamatsu, K., Tamiya, G., Seishima, M., Umetsu, T., Kato, A., Kawaguchi, M., Hayashi, M., Hozomi, Y., Suzuki, T
  • Organizer: 23rd International Pigment Cell Conference
  • Int'l Joint Research
• [Presentation] ロドデノールユーメラニンは強い酸化促進作用をもつ (2016)
  • Author(s): 伊藤祥輔、黄倉真恵、若松一雅、山下利春
  • Organizer: 第27回日本色素細胞学会学術大会
  • Place of Presentation: 岐阜大学サテライトキャンパス、岐阜市
  • Year and Date: 2016-11-12
• [Presentation] N-acetylcysteine (NAC)は紫外線によるロドデノールの色素細胞障害性増強効果を軽減する (2016)
  • Author(s): 後藤典子、辻本昌理子、永井宏、正木太朗、伊藤祥輔、若松一雅、錦織千佳子
  • Organizer: 第27回日本色素細胞学会学術大会
  • Place of Presentation: 岐阜大学サテライトキャンパス、岐阜市
  • Year and Date: 2016-11-12
• [Presentation] カテコールアミン代謝物のオルトキノン体の反応性の比較 (2016)
  • Author(s): 若松一雅、山中佑太、田中ひとみ、小鹿一、伊藤祥輔
  • Organizer: 第27回日本色素細胞学会学術大会
  • Place of Presentation: 岐阜大学サテライトキャンパス、岐阜市
  • Year and Date: 2016-11-12
• [Presentation] The Metabolic Fate of ortho-Quinones Derived from Catecholamine Metabolites. (2016)
  • Author(s): Wakamatsu, K., Yamanaka, Y., Tanaka, H., Ojika, M., Ito, S.
  • Organizer: 20th European Society of Pigment Cell Research Meeting
  • Place of Presentation: Milan, Italy
  • Year and Date: 2016-09-11
  • Int'l Joint Research / Invited
• [Presentation] The Metabolic Fate of ortho-Quinones Derived from Catecholamine Metabolites. (2016)
  • Author(s): Ito, S., Yamanaka, Y., Ojika, M., Wakamatsu, K.
  • Organizer: 20th European Society of Pigment Cell Research Meeting
  • Place of Presentation: Italy, Milan
  • Year and Date: 2016-09-11
  • Int'l Joint Research / Invited
• [Presentation] メラニン酸性細胞におけるロドデノールの代謝 (2015)
  • Author(s): 伊藤祥輔、黄倉真恵、山下利春、小鹿一、中西由紀子、W. Gerwat、L. Kolbe、若松一雅
  • Organizer: 26回日本色素細胞学会学術大会
  • Place of Presentation: 札幌医科大学、札幌
  • Year and Date: 2015-11-14
• [Presentation] マウスの毛色突然変異遺伝子、スレーティーはメラノサイトにおける黄色メラニン生成には影響しない (2015)
  • Author(s): 広部知久、伊藤祥輔、若松一雅
  • Organizer: 26回日本色素細胞学会学術大会
  • Place of Presentation: 札幌医科大学、札幌
  • Year and Date: 2015-11-14
• [Book] 色素細胞ー基礎から臨床へー 第2版 (2015)
  • Author(s): 若松一雅、伊藤祥輔
  • Total Pages: 310
  • Publisher: 慶應義塾大学出版会