Biosynthetic pathway to neuromelanin and its aging process

• Project/Area Number: 24500450
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Fujita Health University
• Principal Investigator: WAKAMATSU Kazumasa 藤田保健衛生大学, 医療科学部, 教授 (80131259)
• Co-Investigator(Kenkyū-buntansha): ITO Shosuke 藤田保健衛生大学, 名誉教授 (70121431)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ニューロメラニン / 黒質 / 青斑核 / 化学分析 / ノルエピネフリン / ドーパミン / パーキンソン病 / 国際情報交換 / イタリア / アメリカ / 化学分解反応 / ヨウ化水素還元

Outline of Final Research Achievements

Neuromelanin (NM) occurs in dopaminergic neurons of the substantia nigra (SN) and in noradrenergic neurons of the locus coeruleus (LC). HPLC analysis after HI hydrolysis of natural NM detected AHPEA, AHPAA and AHEB, which confirmed that SN-NM and LC-NM contain melanin derived not only from DA and NE, but also from several other catecholic metabolites, such as DOPA, DOPAC, DOMA, DOPE and DOPEG, in addition to the corresponding Cys-derivatives in varying degrees. However, HI hydrolysis showed that LC-NM produced the same degradation products as were detected in SN-NM. Thus, we needed to develop a new chemical detection method to validate the existence of NE in LC-NM. HCl hydrolysis of LC-NM in the presence of thioglycolic acid yields new products arising from substitution of the hydroxyl group by thioglycolic acid at the benzyl position of NE and cysteinyl-NE. This is the first chemical evidence showing that NE and cysteinyl-NE are incorporated into LC-NM.

Research Products

• [Journal Article] Reduction of the nitro group to amine by hydroidoic acid to synthesize o-aminophenol derivatives as putative degradative markers of neuromelanin. (2014)
  • Author(s): Wakamatsu, K., Tanaka, H., Tabuchi, K., Ojika, M., Zucca, F.A., Zecca, L., Ito, S.
  • Journal Title: Molecules Volume: 19 Issue: 6 Pages: 8039-8050
  • DOI: 10.3390/molecules19068039
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] TLR4 and NLRP3 inflammasome activation in monocytes by N-propionyl cysteaminylphenol-maleimide-dextran (NPCMD). (2014)
  • Author(s): Mizote, Y., Wakamatsu, K., Ito, S., Uenaka, A., Ohue, Y., Kurose, K., Isobe, M., Ito, A., Tamura, Y., Honda, H., Yamashita, T., Nohara, S., Oka, M., Jimbow, K., Nakayama, E.
  • Journal Title: J. Dermatol. Sci. Volume: 73 Issue: 3 Pages: 76-87
  • DOI: 10.1016/j.jdermsci.2013.11.006
  • Peer Reviewed
• [Journal Article] Sex-specific phenotype integration: endocrine profiles, coloration and behavior in fledgling boobies. (2014)
  • Author(s): Fargallo, J.A., Velando, A., L., Lopez-Rull, I., Ganan, N., Lifshiz, N., Wakamatsu, K., Torres, R.
  • Journal Title: Behavioral Ecology Volume: 25 Issue: 1 Pages: 76-87
  • DOI: 10.1093/beheco/art088
  • Peer Reviewed
• [Journal Article] Heterospecific female mimicry in ficedula flycatchers. (2014)
  • Author(s): Calhim, S., Adamik, P., Jarvisto, P, P., Leskinen, P., Torok, J., Wakamatsu, K., Laaksonen, T.
  • Journal Title: J. Evol. Biol. Volume: 27 Issue: 3 Pages: 660-666
  • DOI: 10.1111/jeb.12328
  • Peer Reviewed
• [Journal Article] Variants in melanogenesis-related genes associate with skin cancer risk among Japanese populations. (2014)
  • Author(s): Yoshizawa J, Abe Y, Oiso N, Fukai K, Hozumi Y, Nakamura T, Narita T, Motokawa T, Wakamatsu K, Ito S, Kawada A, Tamiya G, Suzuki T
  • Journal Title: J Dermatol Volume: 41 Issue: 4 Pages: 296-302
  • DOI: 10.1111/1346-8138.12432
  • Peer Reviewed
• [Journal Article] Buthionine sulfoximine diverts the melanogenesis pathway toward the production of more soluble and degradable pigments. (2014)
  • Author(s): Galvan, I., Wakamatsu, K., Alonso-Alvarez, C., Solano, F.
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 24 Issue: 9 Pages: 2150-2154
  • DOI: 10.1016/j.bmcl.2014.03.031
  • Peer Reviewed
• [Journal Article] HPLC estimation of cross-linking of dihydroxyindole moiety in eumelanin. (2013)
  • Author(s): Ito, S., Wakamatsu, K., Glass, K., Simon, J. D.
  • Journal Title: Anal. Biochem. Volume: 434 Issue: 2 Pages: 221-225
  • DOI: 10.1016/j.ab.2012.12.005
  • Peer Reviewed
• [Journal Article] Photoaging of human retinal pigment epithelium is accompanied by oxidative modifications of its eumelanin (2013)
  • Author(s): S Ito, A Pilat, W Gerwat, CMB Skumatz, M Ito, A Kiyono, A Zadlo, Y Nakanishi, L Kolbe, JM Burke, T Sarna, K Wakamatsu
  • Journal Title: Pigment Cell Melanoma Res Volume: 26 Issue: 3 Pages: 357-366
  • DOI: 10.1111/pcmr.12078
  • Peer Reviewed
• [Journal Article] Sexual dimorphism in melanin pigmentation, feather coloration and its heritability in the barn swallow (Hirundo rustica). (2013)
  • Author(s): Saino, N., Romano, M., Rubolini, D., Teplitsky, C., Ambrosini, R., Caprioli, M., Canova, L., Wakamatsu, K.
  • Journal Title: Plos One Volume: 8 Issue: 2 Pages: e58024-e58024
  • DOI: 10.1371/journal.pone.0058024
  • Peer Reviewed
• [Journal Article] Viability is associated with melanin-based colouration in the barn swallow (Hirundo rustica). (2013)
  • Author(s): Saino, N., Romano, M., Rubolini, D., Ambrosini, R., Caprioli, M., Milzani, A., Costanzo, A., Colombo, G., Canova, L., Wakamatsu, K.
  • Journal Title: Plos One Volume: 8 Issue: 4 Pages: e60426-e60426
  • DOI: 10.1371/journal.pone.0060426
  • Peer Reviewed
• [Journal Article] Melanoma-targeted chemo-thermotherapy and in situ peptide immunotherapy through HSP production by using melanogenesis substrate, NPrCAP and magnetite nanoparticles. (2013)
  • Author(s): Jimbow, K.
  • Journal Title: J. Skin Cancer Volume: 2013 Pages: 174-180
  • DOI: 10.1155/2013/742925
  • Peer Reviewed
• [Journal Article] Vibrational characterization of pheomelanin and trichochrome F by Raman spectroscopy. (2013)
  • Author(s): Galvan, I., Jorge, A., Solano, F., Wakamatsu, K.
  • Journal Title: Spectrochimica Acta Part A Molecular and Biomolecular Spctroscopy Volume: 110 Pages: 55-59
  • DOI: 10.1016/j.saa.2013.03.027
  • Peer Reviewed
• [Journal Article] The mouse ruby-eye 2d (ru2d/Hps5ru2-d) allele inhibits eumelanin but not pheomelanin synthesis. (2013)
  • Author(s): Hirobe, T., Ito, S., Wakamatsu, K.
  • Journal Title: Pigment Cell Melanoma Res. Volume: 26 Issue: 5 Pages: 723-726
  • DOI: 10.1111/pcmr.12118
  • Peer Reviewed
• [Journal Article] Melanins and melanogenesis: methods, standards, protocols (2013)
  • Author(s): d’Ischia, M., Wakamatsu, K., Napolitano, A., Briganti, S., Garcia-Borron, J-C., Kovacs, D., Meredith, P., Pezzella, A., Picardo, M., Sarna, T., Simon, J.D., Ito, S.
  • Journal Title: Pigment Cell Melanoma Res. Volume: 26 Issue: 5 Pages: 616-633
  • DOI: 10.1111/pcmr.12121
  • Peer Reviewed
• [Journal Article] Sexually dimorphic melanin-based colour polymorphism, feather melanin content, and wing feather in the barn owl ‘Tyto alba’. (2013)
  • Author(s): Roulin, A., Mangels, J., Wakamatsu, K., Bachmann, T.
  • Journal Title: Biol. J. the Linnean Soc. Volume: 109 Issue: 3 Pages: 562-573
  • DOI: 10.1111/bij.12078
  • Peer Reviewed
• [Journal Article] Adaptation of pelage color and pigment variations in Israel subterranean blind mole rats, Splax ehrenbergi. (2013)
  • Author(s): Singaravelan, N., Ratz, S., Tzur, S., Belifante, S., Pavlicek, T., Beiles, A., Ito, S., Wakamatsu, K., Nevo, E.
  • Journal Title: Plos One Volume: 8 Issue: 7 Pages: e69346-e69346
  • DOI: 10.1371/journal.pone.0069346
  • Peer Reviewed
• [Journal Article] Raman Spectroscopy as a non-invasive technique for the quantification of melanins in feathers and hairs. (2013)
  • Author(s): Galvan, I., Jorge, A., Ito, K., Tabuchi, K., Solano, F., Wakamatsu, K.
  • Journal Title: Pigment Cell melanoma Res. Volume: 26 Pages: 917-923
  • Peer Reviewed
• [Journal Article] Neutral pH and copper ions promote eumelanogenesis after the dopachrome stage (2013)
  • Author(s): S Ito, N Suzuki, S Takebayashi, S Commo, K Wakamatsu
  • Journal Title: Pigment Cell Melanoma Res Volume: 26 Issue: 6 Pages: 819-825
  • DOI: 10.1111/pcmr.12137
  • Peer Reviewed
• [Journal Article] Reptiles produce pheomelanin: Evidence in the Eastern Hermann’s Tortoise (Eurotestudo boettgeri). (2013)
  • Author(s): Roulin, A., Mafli, A., Wakamatsu, K.
  • Journal Title: J. Herpetol. Volume: 47 Issue: 2 Pages: 258-261
  • DOI: 10.1670/12-028
  • Peer Reviewed
• [Journal Article] Melanin characterization suggests that the ‘brown’ phenotype in alpaca (Vicugna pacos) is predominantly pheomelanic. (2013)
  • Author(s): Cransberg R., Wakamatsu K., Munyard K.
  • Journal Title: Small Ruminant Res. Volume: 114 Issue: 2-3 Pages: 240-246
  • DOI: 10.1016/j.smallrumres.2013.07.004
  • Peer Reviewed
• [Journal Article] Impact of diagenesis and maturation on the survival of eumelanin in the fossil record (2013)
  • Author(s): K Glass, S Ito, PR Wilby, T Sota, A Nakamura, CR Bowers, KE Miller, S Dutta, RE Summons, DEG Briggs, K Wakamatsu, JD Simon
  • Journal Title: Org Geochem Volume: 64 Pages: 29-37
  • DOI: 10.1016/j.orggeochem.2013.09.002
  • Peer Reviewed
• [Journal Article] The mouse brown (b/Tyrp1b) allele does not affect pheomelanin synthesis in mice (2013)
  • Author(s): T Hirobe, S Ito, K Wakamatsu, Y Kawa, H Abe
  • Journal Title: Zool Sci Volume: 31 Issue: 2 Pages: 53-63
  • DOI: 10.2108/zsj.31.53
  • NAID: 40019989060
  • Peer Reviewed
• [Journal Article] メラニンの化学 微量分析法の開発とUVAおよび加熱によるメラニンの分解反応 (2013)
  • Author(s): 若松一雅、伊藤祥輔
  • Journal Title: Aesthertic Dermatology Volume: 23 Pages: 63-73
  • Peer Reviewed
• [Journal Article] メラニンの化学 化学的微量分析法の開発とその応用例 (2013)
  • Author(s): 若松一雅
  • Journal Title: Visual Dermatology Volume: 12 Pages: 601-607
  • Peer Reviewed
• [Journal Article] Photoaging of human retinal pigment epithelium is accompanied by oxidative modification of its eumelanin (2013)
  • Author(s): Ito, S., Pilat, A., Gerwat W., Skumatz, C.M.B., Ito, M., Kiyono, A., Zadlo, A., Nakanishi, Y., Kolbe, L., Burke, J.M., Sarna, T., Wakamatsu, K.
  • Journal Title: Pigment Cell Melanoma Res Volume: 26 Pages: 357-366
  • Peer Reviewed
• [Journal Article] Biosynthetic pathway to neuromelanin and its aging process (2012)
  • Author(s): Wakamatsu, K., Murase, T., Zucca, F.A., Zecca, L., Ito, S.
  • Journal Title: Pigment Cell Melanoma Res. Volume: 25 Pages: 792-803
  • Peer Reviewed
• [Journal Article] Neuromelanins of human brain have soluble and insoluble components with dolichols attached to the melanic structure. (2012)
  • Author(s): Engelen, M., Vanna, R., Bellei, C., Zucca, F. A., Wakamatsu, K., Monzani, E., Ito. S., Casella, L., Zecca, L.
  • Journal Title: PLoS One Volume: 7 Issue: 11 Pages: e48490-e48490
  • DOI: 10.1371/journal.pone.0048490
  • Peer Reviewed
• [Journal Article] UVA-induced oxidation degradation of melanins: Fission of indole moiety in eumelanin and conversion to benzothiazole moiety in pheomelanin (2012)
  • Author(s): Wakamatsu, K., Nakanishi, Y., Miyazaki, N., Kolbe, L., Ito, S.
  • Journal Title: Pigment Cell Melanoma Res. Volume: 25 Pages: 434-445
  • Peer Reviewed
• [Journal Article] Direct chemical evidence for eumelanin pigment from the Jurassic period. (2012)
  • Author(s): Glass, K., Ito, S., Wilby, P.R., Sota, T., Nakamura, A., Bowers, C.R., Vinther, J., Dutta, S., Summons, R., Briggs, D.E., Wakamatsu, K., Simon, J.D.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 109 Pages: 10218-10223
  • Peer Reviewed
• [Presentation] Elaboration of Approach to Structure of Neuromelanin Present in Various Brain Regions as Studied by Chemical Degradative Methods (2014)
  • Author(s): Kazumasa Wakamatsu
  • Organizer: XXII International Pigment Cell Conference
  • Place of Presentation: Singapore
  • Year and Date: 2014-09-04 – 2014-09-07
  • Invited
• [Presentation] Convenient synthetic method of putative degradative markers to identify various catecholic metabolites in addition to dopamine and norepinephrine incorporated in neuromelanin (2014)
  • Author(s): Keisuke Tabuchi, Hitomi Tanaka, Makoto Ojika, Fabio A. Zucca, Luigi Zecca, Shosuke Ito, Kazumasa Wakamatsu
  • Organizer: XXII International Pigment Cell Conference
  • Place of Presentation: Singapore
  • Year and Date: 2014-09-04 – 2014-09-07
• [Presentation] 酸化ストレスと抑うつに関する一考察 (2014)
  • Author(s): 伊藤康宏、原口紗衣、伴光雅、伊藤祥輔、若松一雅
  • Organizer: 第24回生物試料分析科学会年次学術集会
  • Place of Presentation: 鈴鹿医療科学大学千代崎キャンパス、鈴鹿市
• [Presentation] 様々な脳領域に存在するニューロメラニンの化学分解法を用いた構造解析 (2013)
  • Author(s): 若松一雅、田渕啓佑、田中ひとみ、Fabio A. Zecca、Luigi Zecca、伊藤祥輔
  • Organizer: 第25回日本色素細胞学会学術大会
  • Place of Presentation: 大阪大学、吹田市
• [Presentation] 中性pHと銅イオンはドーパクロム以降のユーメラニン形成を促進する (2013)
  • Author(s): 伊藤祥輔、鈴木菜摘、竹林史織、Stéphane Commo、若松一雅
  • Organizer: 第25回日本色素細胞学会学術大会
  • Place of Presentation: 大阪大学、吹田市
• [Presentation] マウスルビーアイ2d遺伝子は黒色メラニン生成を抑制するが黄色メラニン生成には影響しない (2013)
  • Author(s): 広部知久、伊藤祥輔、若松一雅
  • Organizer: 第84回日本動物学科
  • Place of Presentation: 岡山大学、岡山市
• [Presentation] チロシナーゼのS-パルミトイル化はその分解を制御しメラニン生成を調整する (2013)
  • Author(s): ：仁木洋子、深田正紀、深田優子、奥 慎一郎、岡村千絵子、竹内聖二、若松一雅、伊藤祥輔、錦織千佳子、Lieve Declercq、Daniel B. Yarosh、齋藤尚亮
  • Organizer: 第25回日本色素細胞学会学術大会
  • Place of Presentation: 大阪大学、吹田市
• [Presentation] 量子化学計算からの5,6-dihydroxyindoleの光吸収特性の重合度と酸化度への依存性 (2013)
  • Author(s): 増田吉弘、奥田英和、小池謙造、門田圭司、中村隆仁、若松一雅、伊藤祥輔、宗田孝之
  • Organizer: 第25回日本色素細胞学会学術大会
  • Place of Presentation: 大阪大学、吹田市
• [Presentation] 新規製剤N-propionyl cysteaminylphenol-maleimid-dextran (NPCMD)による免疫応答賦活効果 (2013)
  • Author(s): 横手雄、若松一雅、伊藤祥輔、上中明子、黒瀬浩史、大植祥弘、西尾祐実、岡三喜男、神保孝一、中山睿一
  • Organizer: 第17回日本がん免疫学会総会
  • Place of Presentation: ANAクラウンプラザホテル宇部、宇部市
• [Presentation] Degradative approach to the structure of neuromelanins. (2013)
  • Author(s): K. Wakamatsu, K. Tabuchi, H. Tanaka, S. Ito
  • Organizer: 18th Meeting of the European Society for Pigment Cell Research
  • Place of Presentation: Lisbon, Portugal
• [Presentation] (Photo)degradation of eumelanin and pheomelanin and its physiological implication (2013)
  • Author(s): Ito, S., Wakamatsu, K
  • Organizer: 18th Meeting of the European Society for Pigment Cell Research
  • Place of Presentation: Lisbon, Portugal
• [Presentation] UVAによるメラニンの酸化分解 (2012)
  • Author(s): 若松一雅、中西由紀子、宮崎成美、Ludger Kolbe、伊藤祥輔
  • Organizer: 日本色素細胞学会
  • Place of Presentation: 長浜バイオ大学
• [Presentation] ユーメラニン中のジヒドロキシインドール構造の加熱による架橋形成 (2012)
  • Author(s): 伊藤祥輔、若松一雅、Keely Glass、John D. Simon
  • Organizer: 日本色素細胞学会
  • Place of Presentation: 長浜バイオ大学
• [Presentation] 量子化学計算からのDHIとDHICAの二量体構造解析および振動解析 (2012)
  • Author(s): 奥田英和、兵庫亮佑、若松一雅、伊藤祥輔、宗田孝之
  • Organizer: 日本色素細胞学会
  • Place of Presentation: 長浜バイオ大学
• [Presentation] 量子化学計算からの5,6-dihydroxyindole四量体の構造解析 (2012)
  • Author(s): 増田吉弘、奥田英和、小池謙造、門田圭司、中村隆仁、若松一雅、伊藤祥輔、宗田孝之
  • Organizer: 日本色素細胞学会
  • Place of Presentation: 長浜バイオ大学
• [Presentation] DHICA二量体と三量体の立体構造と振動分光学的特性 (2012)
  • Author(s): 兵庫亮佑、名取千沙、中村厚、奥田英和、小鹿一、若松一雅、伊藤祥輔、宗田孝之
  • Organizer: 日本色素細胞学会
  • Place of Presentation: 長浜バイオ大学
• [Presentation] OCA2多型は日本人集団において皮膚色と皮膚癌リスクに関係する (2012)
  • Author(s): 吉澤順子、阿部優子、穂積豊、大磯直毅、成田智彦、川田暁、深井和吉、本川智紀、若松一雅、伊藤祥輔、中村智洋、田宮元、鈴木民夫
  • Organizer: 日本色素細胞学会
  • Place of Presentation: 長浜バイオ大学