研究テーマ

「アルツハイマー病病態解明」と「様々な病態関連物質の簡便な化学的可視化」

私たちの研究室では薬学研究や基礎医学研究から実践的な医療応用を目指します。また、その一方で、逆に臨床医学から生まれる疑問を基礎研究や薬学の研究技術で解明します。対象疾患はアルツハイマー病や自己免疫性脳炎です。また、一方、疾患を特定せず病態関連物質の簡便な化学的測定法の開発にも取り組んでおります。
 

キーワード

アルツハイマー病、キサンチン系色素、フルオレセイン、アミロイドβ蛋白、γセクレターゼ、非天然アミノ酸の遺伝的取り込み、光親和性クロスリンク、エクソサイト、自己免疫性脳炎
 

配属学生

大学院生 0名
学部学生 6年次生:11名、5年次生:13名、4年次生:13名

所属教員

研究内容(薬物治療学II研究室)

(1)アルツハイマー病の分子病態解明及びその応用に関する研究

アルツハイマー病病原物質アミロイドβを産生する酵素であるγセクレターゼの研究を長年行ってまいりました。次の(2)の技術を用いて、基質結合部位をアミノ酸レベルでのマッピングを行い、以下の発見をしてきました。今後、それを応用・発展させる研究を行います。
 
①エクソサイトと呼ばれる基質結合部位

②家族性アルツハイマー病のプレセニリン変異体での酵素と基質のアミノ酸レベルの相互作用の変化

③基質のエクソサイトから触媒部位へのダイナミックな輸送

参考文献

  1. Fukumori, A., Feilen, L. P., and Steiner, H. (2020) Substrate recruitment by γ-secretase. Semin. Cell Dev. Biol. 10.1016/j.semcdb.2020.03.006
  2. Trambauer, J., Fukumori, A., and Steiner, H. (2020) Pathogenic Aβ generation in familial Alzheimer’s disease: novel mechanistic insights and therapeutic implications. Curr. Opin. Neurobiol. 61, 73–81
  3. Steiner, H., Fukumori, A., Tagami, S., and Okochi, M. (2018) Making the final cut : pathogenic amyloid- β peptide generation by γ -secretase. Cell Stress. 2, 292–310
  4. Trambauer, J., Fukumori, A., Kretner, B., and Steiner, H. (2017) Analyzing Amyloid-β Peptide Modulation Profiles and Binding Sites of γ-Secretase Modulators. Methods Enzymol. 584, 157–183
  5. Fukumori, A., and Steiner, H. (2016) Substrate recruitment of γ‐secretase and mechanism of clinical presenilin mutations revealed by photoaffinity mapping. EMBO J. 35, 1628–1643

(2)非天然アミノ酸の遺伝的取り込み法を用いたアミノ酸レベルでの相互作用の解析とその応用

図のように☆の一アミノ酸に結合する蛋白を光照射によるクロスリンク技術により可視化できる。
☆の部位に非天然アミノ酸を取り込むために、人工的なtRNA、tRNA synthetaseを用いる。下図、左は通常のメチオニン、右は非天然アミノ酸pBpaの取り込み装置の模式図。

 

参考文献

  1. Fukumori, A., and Steiner, H. (2016) Substrate recruitment of γ‐secretase and mechanism of clinical presenilin mutations revealed by photoaffinity mapping. EMBO J. 35, 1628–1643
  2. Chávez‐Gutiérrez, L., and De Strooper, B. (2016) Probing γ‐secretase–substrate interactions at the single amino acid residue level. EMBO J. 35, 1597–1599
  3. Chin, J. W., Martin, A. B., King, D. S., Wang, L., and Schultz, P. G. (2002) Addition of a photocrosslinking amino acid to the genetic code of Escherichiacoli. Proc. Natl. Acad. Sci. U. S. A. 99, 11020–4
  4. Fukumori, A., Trambauer, J., Feilen, L. P., and Steiner, H. (2018) Identifizierung von Substratbindestellen in der γ-Sekretase. BioSpektrum. 24, 34–36 次のホームページで閲覧可能 http://rdcu.be/GLyg

(3) 病態関連分子及びその相互作用の化学的可視化に関する研究

・既知の病態関連分子などの簡便な測定法の開発
 病態と関連する種々の物質(腫瘍マーカー、腎疾患マーカー、金属イオン、活性酸素および過酸化物、アルデヒド類,糖類、チオール化合物、
 医薬品など)の新規高感度分析法の開発について キサンテン系色素誘導体(下図参照)と金属との三元錯体生成反応などをもとに検討する。
・生理活性作用を有する金属錯体の創製に関する研究
 天然に存在する色素などキサンテン系色素以外の金属錯体の創製とその特性並びに化学構造の検索、更には創製した金属錯体の生理活性
 作用に関する探索について検討する。
文献:
1.Yamaguchi T., Hoshino M., Miyachi K., Kamino S., Nakahara R., Doi M., Asano M., Matsumura H., Fujita Y., (2016) Crystal
 Structure of o-Carboxyphenylfluorone as a Multifunctional Dye. X-ray Structure Analysis online, 32, 9-10
 次のホームページで閲覧可能 https://www.jstage.jst.go.jp/article/xraystruct/32/0/32_9/_article/-char/ja/
2.Ikeda C., Nakahara R., Nishioka Y., Kurokawa H., Yamaguchi T., Fujita Y. (2009) Spectrophotometric Determination of
 Nitrite Ion with Pyrogallol Red-Molybdenum(VI) Complex. BUNSEKI KAGAKU, 8, 675–379

(4) その他、

・NMDA受容体自己抗体脳炎の自己抗体の検出法の開発
 大阪急性期・総合医療センター 松永秀典先生との共同研究

代表的論文

2022年度

  1. Feilen LP., Chen SY., Fukumori A., Feederle R., Zacharias M., Steiner H.(2022)Active site geometry stabilization of a presenilin homolog by the lipid bilayer promotes intramembrane proteolysis. Elife. 11:e76090.
  2. Yanagida K., Maruyama R., Tagami S., Kudo T., Okochi M., Fukumori A.(2023)APLP2 is predominantly cleaved by β-secretase and γ-secretase in the human brain. Psychogeriatrics. 23(2):311-318.
  3. Matsunaga H., Fukumori A., Mori K., Morihara T., Sato S., Kitauchi K., Yanagida K., Taguchi K., Honda T., Tomonaga K.(2023)Ribavirin Treatment for Severe Schizophrenia with Anti-Borna Disease Virus 1 Antibodies 30 Years after Onset. Case Rep Psychiatry. 2023:4899364.

2021年度

  1. Shinohara, M., Hirokawa, J., Shimodaira, A., Tashiro, Y., Suzuki, K., Gheni, G., Fukumori, A., Matsubara, T., Morishima, M., Saito, Y., Murayama, S., Sato, N. (2021) ELISA Evaluation of Tau Accumulation in the Brains of Patients with Alzheimer Disease. J Neuropathol Exp Neurol. 80(7):652-662.
  2. Shinohara, M., Kikuchi, M., Onishi-Takeya, M., Tashiro, Y., Suzuki, K., Noda, Y., Takeda, S., Mukouzono, M., Nagano, S., Fukumori, A., Morishita, R., Nakaya, A., Sato, N. (2021) Upregulated expression of a subset of genes in APP;ob/ob mice: Evidence of an interaction between diabetes-linked obesity and Alzheimer's disease. FASEB Bioadv. 3(5):323-333.
  3. Suzuki, K., Shinohara, M., Uno, Y., Tashiro, Y., Gheni, G., Yamamoto, M., Fukumori, A., Shindo, A., Mashimo, T., Tomimoto, H., Sato, N. (2021) Deletion of B-cell translocation gene 2 (BTG2) alters the responses of glial cells in white matter to chronic cerebral hypoperfusion. J Neuroinflammation. 18(1):86.
  4. Adachi, H., Yamamoto, R., Fujino, R., Kanayama, D., Sakagami, Y., Akamine, S., Marutani, N., Yanagida, K., Mamiya, Y., Koyama, M., Shigedo, Y., Sugita, Y., Mashita, M., Nakano, N., Watanabe, K., Ikeda, M., Kudo, T. (2021) Association of weekday-to-weekend sleep differences and stress response among a Japanese working population: a cross-sectional study. Sleep Med. 82:159-164.

2020年度

  1. Fukumori, A., Feilen, L. P., and Steiner, H. (2020) Substrate recruitment by γ-secretase. Semin. Cell Dev. Biol. 105:54-63
  2. Trambauer, J., Fukumori, A., and Steiner, H. (2020) Pathogenic Aβ generation in familial Alzheimer’s disease: novel mechanistic insights and therapeutic implications. Curr. Opin. Neurobiol. 61: 73–81
  3. Shinohara M, Tashiro Y, Suzuki K, Fukumori A, Bu G, Sato N. (2020) Interaction between APOE genotype and diabetes in cognitive decline. Alzheimers Dement (Amst). 12(1):e12006.
  4. Shinohara M, Tashiro Y, Shinohara M, Hirokawa J, Suzuki K, Onishi-Takeya M, Mukouzono M, Takeda S, Saito T, Fukumori A, Saido TC, Morishita R, Sato N. (2020) Increased levels of Aβ42 decrease the lifespan of ob/ob mice with dysregulation of microglia and astrocytes. FASEB J. 34(2):2425-2435.
  5. Trambauer J, Rodríguez Sarmiento RM, Fukumori A, Feederle R, Baumann K, Steiner H. (2020) Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation. EMBO Rep. 21(1):e47996.
  6. Akamine S, Marutani N, Kanayama D, Gotoh S, Maruyama R, Yanagida K, Sakagami Y, Mori K, Adachi H, Kozawa J, Maeda N, Otsuki M, Matsuoka T, Iwahashi H, Shimomura I, Ikeda M, Kudo T. (2020) Renal function is associated with blood neurofilament light chain level in older adults. Sci Rep. 10(1):20350.
  7. Matsuhisa K, Saito A, Cai L, Kaneko M, Okamoto T, Sakaue F, Asada R, Urano F, Yanagida K, Okochi M, Kudo Y, Matsumoto M, Nakayama KI, Imaizumi K. (2020) Production of BBF2H7-derived small peptide fragments via endoplasmic reticulum stress-dependent regulated intramembrane proteolysis. FASEB J. 34(1):865-880.

2019年度

  1. Mentrup, T., Theodorou, K., Cabrera-Cabrera, F., Helbig, A. O., Happ, K., Gijbels, M., Gradtke, A.-C., Rabe, B., Fukumori, A., Steiner, H., Tholey, A., Fluhrer, R., Donners, M., and Schröder, B. (2019) Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis. J. Exp. Med. 216 (4): 807–830.

2018年

  1. Fukumori, A., Trambauer, J., Feilen, L. P., and Steiner, H. (2018) Identifizierung von Substratbindestellen in der γ-Sekretase. BioSpektrum. 24, 34–36
  2. Matsunaga, H., Fukumori, A., Mori, K., Honda, T., Uema, T., and Tomonaga, K. (2018) Two neuropsychiatric cases seropositive for bornavirus improved by ribavirin. Jpn. J. Infect. Dis. 71, 338–342
  3. Steiner, H., Fukumori, A., Tagami, S., and Okochi, M. (2018) Making the final cut : pathogenic amyloid- β peptide generation by γ -secretase. Cell Stress. 2, 292–310

2017年

  1. Schlepckow, K., Kleinberger, G., Fukumori, A., Feederle, R., Lichtenthaler, S. F., Steiner, H., and Haass, C. (2017) An Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol. Med. 9, 9:1356-1365
  2. Tagami S, Yanagida K, Kodama TS, Takami M, Mizuta N, Oyama H, Nishitomi K, Chiu YW, Okamoto T, Ikeuchi T, Sakaguchi G, Kudo T, Matsuura Y, Fukumori A, Takeda M, Ihara Y, Okochi M. (2017) Semagacestat Is a Pseudo-Inhibitor of γ-Secretase. Cell Rep. 21(1):259-273.
  3. Trambauer, J., Fukumori, A., Kretner, B., and Steiner, H. (2017) Analyzing Amyloid-β Peptide Modulation Profiles and Binding Sites of γ-Secretase Modulators. Methods Enzymol. 584, 157–183
  4. Asano, M., Tanaka, S., Sakaguchi, M., Matsumura, H., Yamaguchi, T., Fujita, Y., and Tabuse, K. (2017) Normothermic Microwave Irradiation Induces Death of HL-60 Cells through Heat-Independent Apoptosis. Sci. Rep. 7, 11406
  5. Asano, M., Sakaguchi, M., Tanaka, S., Kashimura, K., Mitani, T., Kawase, M., Matsumura, H., Yamaguchi, T., Fujita, Y., and Tabuse, K. (2017) Effects of Normothermic Conditioned Microwave Irradiation on Cultured Cells Using an Irradiation System with Semiconductor Oscillator and Thermo-regulatory Applicator. Sci. Rep. 7, 41244
  6. Mizuta N, Yanagida K, Kodama T, Tomonaga T, Takami M, Oyama H, Kudo T, Ikeda M, Takeda M, Tagami S, Okochi M. (2017) Identification of Small Peptides in Human Cerebrospinal Fluid upon Amyloid-β Degradation. Neurodegener Dis. 17(2-3):103-109.

     

2016年

  1. Fukumori, A., and Steiner, H. (2016) Substrate recruitment of γ‐secretase and mechanism of clinical presenilin mutations revealed by photoaffinity mapping. EMBO J. 35, 1628–1643
  2. Huettl, S., Helfrich, F., Mentrup, T., Held, S., Fukumori, A., Steiner, H., Saftig, P., Fluhrer, R., and Schroeder, B. (2016) Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74. Biochem. J. 473, 1405–1422
  3. Fleck, D., Voss, M., Brankatschk, B., Giudici, C., Hampel, H., Schwenk, B., Edbauer, D., Fukumori, A., Steiner, H., Kremmer, E., Haug-Kröper, M., Rossner, M. J., Fluhrer, R., Willem, M., and Haass, C. (2016) Proteolytic Processing of Neuregulin 1 Type III by Three Intramembrane-cleaving Proteases. J. Biol. Chem. 291, 318–33
  4. Kretner, B., Trambauer, J., Fukumori, A., Mielke, J., Kuhn, P.-H., Kremmer, E., Giese, A., Lichtenthaler, S. F., Haass, C., Arzberger, T., and Steiner, H. (2016) Generation and deposition of Aβ43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer’s disease. EMBO Mol. Med. 8, 458–65

2015年

  1. Schulte, E. C., Fukumori, A., Mollenhauer, B., Hor, H., Arzberger, T., Perneczky, R., Kurz, A., Diehl-Schmid, J., Hüll, M., Lichtner, P., Eckstein, G., Zimprich, A., Haubenberger, D., Pirker, W., Brücke, T., Bereznai, B., Molnar, M. J., Lorenzo-Betancor, O., Pastor, P., Peters, A., Gieger, C., Estivill, X., Meitinger, T., Kretzschmar, H. A., Trenkwalder, C., Haass, C., and Winkelmann, J. (2015) Rare variants in β-Amyloid precursor protein (APP) and Parkinson’s disease. Eur. J. Hum. Genet. 23, 1328–1333
  2. Tsaktanis, T., Kremling, H., Pavšič, M., von Stackelberg, R., Mack, B., Fukumori, A., Steiner, H., Vielmuth, F., Spindler, V., Huang, Z., Jakubowski, J., Stoecklein, N. H., Luxenburger, E., Lauber, K., Lenarčič, B., and Gires, O. (2015) Cleavage and cell adhesion properties of human epithelial cell adhesion molecule (HEPCAM). J. Biol. Chem. 290, 24574–91