Biosynthetic pathway to neuromelanin and its structural modification in aging : Incorporation of neurotoxic molecules in neuromelanin

2011 Fiscal Year Final Research Report

• Project/Area Number: 21500358
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• 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) ; KATO Yoshimitsu 藤田保健衛生大学, 医療科学部, 准教授 (20121436)
• Project Period (FY): 2009 – 2011
• Keywords: ニューロメラニン / 化学分析 / パーキンソン病 / ドーパミンメラニン / システイニルドーパミンメラニン / 黒質 / 青斑核 / カテコールアミン作動性ニューロン

Research Abstract

The biosynthesis and structure of neuromelanin(NM) still remains poorly understood. Using model compounds of the melanic component of NM prepared by tyrosinase oxidation at various ratios of dopamine(DA) and cysteine(Cys) under physiological conditions, we performed a biosynthetic and biodegradative(aging) study by following the time course of oxidation to NM and the subsequent biodegradation of NM under various heating conditions. By following the time course of the biosynthetic pathway of synthetic NM we found that the neurotoxic molecules are trapped in NM. By comparing the ratios of the degradation markers, natural NM was found to be similar to aged(heated) NM prepared from a 2 : 1 molar ratio of DA and Cys, which can be used as a model of natural NM. A method to prepare synthetic NM that mimics the melanic component of human NM structurally was now established, i. e., tyrosinase oxidation of DA+Cys in a ratio of 2 : 1 followed by heating at 37℃for 40 days. This preparation of model NM should facilitate studies elucidating the physiological roles of NM during the aging process and its roles in the etiology pathogenesis of PD.

Research Products

• [Journal Article] Diversity of human hair pigmentation as studied by chemical analysis of eumelanin and pheomelanin (2011)
  • Author(s): Ito, S., Wakamatsu, K.
  • Journal Title: J. Eur. Acad. Dermatol. Venereol Volume: 25 Pages: 1369-1380
  • Peer Reviewed
• [Journal Article] Usefulness of alkaline hydrogen peroxide oxidation to analyze eumelanin and pheomelanin in various tissue samples : application to chemical analysis of human hair melanins (2011)
  • Author(s): Ito, S., Nakanishi, Y., Valenzuela, R. K., Brilliant, M. H., Kolbe, L., Wakamatsu, K.
  • Journal Title: Pigment Cell Melanoma Res Volume: 24 Pages: 605-618
  • Peer Reviewed
• [Journal Article] Maintenance of immune hyporesponsiveness to melanosomal proteins by DHICA-mediated antioxidation : possible implications for autoimmune vitiligo (2011)
  • Author(s): Liu, X-M., Zhou, Q., Xu, S-Z., Wakamatsu, K., Lei, T-C.
  • Journal Title: Free Radic. Biol. Med Volume: 50 Pages: 1177-1185
  • Peer Reviewed
• [Journal Article] Inactivation of Pmel alters melanosome shape but has only a subtle effect on visible pigmentation (2011)
  • Author(s): Hellstrom, A. R., Watt, B., Fard, S. S., Tenza, D., Mannstriim, Narfstriim, BjOn Ekesten, Ito, S., Wakamatsu, K., Larsson, J., Ulfendahl, M., Kullander, K., Raposo, G., Kerje, S., Hallbiiiik, Marks, M. S., Andersson, L.
  • Journal Title: PLoS Genetics Volume: 7 Pages: e1002285
  • Peer Reviewed
• [Journal Article] Spiny mice modulate eumelanin to pheomelanin ratio to achieve cryptic coloration in "Evolution Canyon" (2010)
  • Author(s): Singaravelan, N., Pavlicek, T., Beharav, A., Wakamatsu, K., Ito, S., Nevo, E.
  • Journal Title: Israel. Plos One Volume: 5 Pages: e8708
  • Peer Reviewed
• [Journal Article] Protection against ultraviolet radiation involves MC1R-mediated non-pigmentary and pigmentary mechanisms in vivo (2010)
  • Author(s): Robinson, S., Dixon, S., August, S., Diffey, B., Wakamatsu, K., Ito, S., Friedmann, P. S., Healy, E.
  • Journal Title: J. Invest. Dermatol Volume: 130 Pages: 1904-1913
  • Peer Reviewed
• [Journal Article] Regulation of DHICA-mediated antioxidation by dopachrome tautomerase : implication for skin pthotoprotection against UVA radiation (2010)
  • Author(s): Jiang, S., Liu, X-M., Dai, X., Zhou, Q., Lei, T-C., Beermann, F., Wakamatsu, K., Xu, S-Z.
  • Journal Title: Free Rad. Biol. Med Volume: 48 Pages: 1144-1151
  • Peer Reviewed
• [Journal Article] Imaging, chemical and spectroscopic studies of the methylation-induced decomposition of melanosome (2010)
  • Author(s): Kempf, V., Wakamatsu, K., Ito, S., Simon, JD.
  • Journal Title: Photochem Photobiol Volume: 86 Pages: 765-771
  • Peer Reviewed
• [Journal Article] Agaritine purified from Agaricus blazei Murrill exerts anti-tumor activity against leukemic cells (2010)
  • Author(s): Endo, M., Beppu, H., Akiyama, H., Wakamatsu, K., Ito, S., Kawamoto, Y., Shimpo, K., Sumiya, T., Koike, T., Matsui, T.
  • Journal Title: Biochim Biophys Acta Pages: 669-673
  • Peer Reviewed
• [Journal Article] Melanocortin 1 receptor genotype : an important determinant of the damage response of Melanocytes to ultraviolet radiation (2010)
  • Author(s): Kadekaro, AL., Leachman, S., Kavanagh, RJ., Swope, V., Cassidy, P., Supp, D., Sartor, M., Schwemberger, S., Babcock, G., Wakamatsu, K., Ito, S., Koshoffer, A., Boissy, RE., Manga, P., Sturm, RA., Abdel-Malek, ZA.
  • Journal Title: The FASEB J Volume: 24 Pages: 3850-3860
  • Peer Reviewed
• [Journal Article] Increased cysteinyldopa plasma levels hint to melanocyte as stress sensor in psoriasis (2010)
  • Author(s): Panzella, L., Wakamatsu, K., Monfrecola, G., Ito, S., Ayala, F., Napolitano, A.
  • Journal Title: Experimental Dermatology Volume: 20 Pages: 288-290
  • Peer Reviewed
• [Journal Article] Human hair melanins : What we have learned and have not learned from mouse coat color pigmentation (2010)
  • Author(s): Ito, S., Wakamatsu, K.
  • Journal Title: Pigment Cell & Melanoma Res Volume: 24 Pages: 63-74
  • Peer Reviewed
• [Journal Article] Chemical analysis of late stages of phaeomelanogenesis : conversion of dihydrobenzothiazine to a benzothiazole structure (2009)
  • Author(s): Wakamatsu, K., Ohtara, K., Ito, S.
  • Journal Title: Pigment Cell Melanoma Res Volume: 22 Pages: 474-486
  • Peer Reviewed
• [Journal Article] Melanins seem to be present everywhere in the body, but for what? (2009)
  • Author(s): Ito, S.
  • Journal Title: Pigment Cell Melanoma Res Volume: 22 Pages: 12-13
  • Peer Reviewed
• [Journal Article] Prolonged treatment of fair-skinned mice with topical forskolin causes persistent tanning and UV protection (2009)
  • Author(s): Spry, ML., Vanover, JC., Scott, T., Abona-Ama, 0., Wakamatsu, K., Ito, S., D' Orazio, JA.
  • Journal Title: Pigment Cell Melanoma Res Volume: 22 Pages: 219-229
  • Peer Reviewed
• [Journal Article] Isomeric cysteinyldopas provide a(photo) degradable bulk component and a robust structural element in red human hair pheomelanin (2009)
  • Author(s): Greco, G., Wakamatsu, K., Panzella, L., Ito S., Napolitano, A., d' Ischia, M.
  • Journal Title: Pigment Cell Melanoma Res Volume: 22 Pages: 319-327
  • Peer Reviewed
• [Journal Article] Comparison of eumelanin and pheomelanin content between cultured uveal melanoma cells and normal uveal melanocytes (2009)
  • Author(s): Hu, DN., Wakamatsu, K., Ito, S., McCormick, SA.
  • Journal Title: Melanoma Res Volume: 19(2) Pages: 75-79
  • Peer Reviewed
• [Journal Article] Current Challenges in understanding melanogenesis : Bridging chemistry, biological control, morphology and function (2009)
  • Author(s): Simon, J. D., Peles, D., Wakamatsu, K., Ito, S.
  • Journal Title: Pigment Cell Melanoma Res Volume: 22 Pages: 563-579
  • Peer Reviewed
• [Journal Article] Stem cell factor rescues tyrosinase expression and pigmentation in discreet anatomic locations in albino mice (2009)
  • Author(s): Vanover, J. C., Spry, M. L., Hamilton, L., Wakamatsu, K., Ito, S., D' Orazio, J. A.
  • Journal Title: Pigment Cell Melanoma Res Volume: 22 Pages: 827-838
  • Peer Reviewed
• [Presentation] Chemistry and biophysics of neuromelanin (2011)
  • Author(s): Wakamatsu, K., Murase, T., Zucca, F. A., Zecca, L., Ito, S.
  • Organizer: XXlst International Pigment Cell Conference(IPCC)
  • Place of Presentation: Bordeaux, France
  • Year and Date: 20110920-24
• [Presentation] Evaluation of alkaline hydrogen peroxide oxidation to analyze eumelanin and pheomelanin (2011)
  • Author(s): Ito, S., Nakanishi, Y., Wakamatsu, K.
  • Organizer: XXlst International Pigment Cell Conference(IPCC)
  • Place of Presentation: Bordeaux, France
  • Year and Date: 20110920-24
• [Presentation] Human hair pigmentation characteristics revealed by melanin determination in human eumelanic hairs of various ethnic origins (2011)
  • Author(s): Commo, S., Wakamatsu, K., Ito, S.
  • Organizer: XX 1 st International Pigment Cell Conference(IPCC)
  • Place of Presentation: Bordeaux, France
  • Year and Date: 20110920-24
• [Presentation] A novel pathway for regulation of pigmentation by glutamate receptor mGluR6 through its action on TRPM1 (2011)
  • Author(s): Devi, S., Markandeya, Y., Maddodi, N., Wakamatsu, K., Ito, S., Balijepalli, R., Setaluri, V.
  • Organizer: XXlst International Pigment Cell Conference(IPCC)
  • Place of Presentation: Bordeaux, France
  • Year and Date: 20110920-24
• [Presentation] ヒト脳内黒質に存在する黒褐色色素ニューロメラニンの生成過程の解明 (2010)
  • Author(s): 村瀬貴也、伊藤祥輔、若松一雅
  • Organizer: 第23回日本色素細胞学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2010-11-28
• [Presentation] 「分かりやすいメラニンの生化学とメラノサイトの生化学」混合型メラニン形成の生化学 (2010)
  • Author(s): 伊藤祥輔
  • Organizer: 第23回日本色素細胞学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2010-11-28
• [Presentation] 子化学計算からの5, 6-dihydroxyindoleとそのカルボキシ誘導体のヘテロニ量体化機構 (2010)
  • Author(s): 奥田英和、若松一雅、伊藤祥輔、宗田孝之
  • Organizer: 第23回日本色素細胞学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2010-11-27
• [Presentation] グルコサミンは3次元ヒト表皮モデルでエンドセリンー1/ステムセルファクター誘導色素沈着をメラノサイトでのCREBシグナルの減少により抑制する (2010)
  • Author(s): 若林雄希、中島弘明、深澤勝則、若松一雅、芋川玄爾
  • Organizer: 第23回日本色素細胞学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2010-11-27
• [Presentation] ルビーアイ2の新規突然変異遺伝子(ru2d/Hps5d)はマウスのメラノサイトの分化を抑制し毛色を薄くするが、L-チロシンはその分化活性を回復させる (2010)
  • Author(s): 広部知久、吉原千尋、竹内栄、阿部宏之、若松一雅、伊藤祥輔、河陽子、相馬良直、溝口昌子
  • Organizer: 第23回日本色素細胞学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2010-11-27
• [Presentation] フェオメラニン生成の後期過程の化学的分析 (2009)
  • Author(s): 若松一雅、太田良和美、伊藤祥輔
  • Organizer: 第22回日本色素細胞学会学術大会
  • Place of Presentation: 福岡
  • Year and Date: 2009-12-05
• [Presentation] 5, 6-dihydroxyindole-2-carboxylicacid二量体の異性体判別:中赤外吸収スペクトル (2009)
  • Author(s): 奥田秀和、中村厚、若松一雅、伊藤祥輔、宗田孝之
  • Organizer: 第22回日本色素細胞学会学術大会
  • Place of Presentation: 福岡
  • Year and Date: 2009-12-05
• [Presentation] N-propionyl-4-S-cysteaminylphenolはメラノーマ細胞にアポトーシスを誘導しマウスB16F1腫瘍の増殖を抑制する (2009)
  • Author(s): 箴井泰江、田村保明、佐藤昇志、若松一雅、伊藤祥輔、井藤彰、本多裕之、黄倉真恵、佐藤亜紀子、山下利春、神保孝一
  • Organizer: 第22回日本色素細胞学会学術大会
  • Place of Presentation: 福岡
  • Year and Date: 2009-12-05
• [Presentation] Chemical structure of neuromelanin : an elucidation to the production process (2009)
  • Author(s): Wakamatsu, K.
  • Organizer: 3rd Asian Society for Pigment Cell Research Meeting
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2009-06-12
• [Presentation] Chemical and biochemical control of mixed melanogenesis (2009)
  • Author(s): Ito, S.
  • Organizer: 3rd Asian Society for Pigment Cell Research Meeting
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2009-06-11
• [Presentation] Serum levels of 5-S-cysteinyldopa are correlated to pigmentation in patients undergoing hemodialysis (2009)
  • Author(s): Murakami, K., Wakamatsu, K., Nakanishi, Y., Yamamoto, K., Kohriyama, N., Hasegawa, M., Tomita, M., Nabeshima, K., Hiki, N., Asano, S., Kawashima, S., Ito, Y., Fujita, Y., Asada, H., Nakai, S., Sugiyama, S., Ito, S.
  • Organizer: World Congress of Nephrology 2009
  • Place of Presentation: Milano, Italy
  • Year and Date: 2009-05-24
• [Book] Structure of Melanins : Melanins and Melanosomes : J. BorovanskST, P. A. Riley(eds) (2011)
  • Author(s): Ito, S., Wakamatsu, K., M. d' Ischia, A. Napolitano, A. Pezzella.
  • Total Pages: 167-185