低分子化合物スクリーニングによるパーキンソン病治療薬開発

2013 Fiscal Year Annual Research Report

• Project/Area Number: 23390232
• Research Institution: Kyoto University
• Principal Investigator: 高橋 良輔 京都大学, 医学(系)研究科(研究院), 教授 (90216771)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: α-シヌクレイン / HTS / パーキンソン病 / 疾患モデルマウス

Research Abstract

α-synuclein(alpha-syn)の産生を低下させる低分子化合物のスクリーニングを行い、のalpha-synの発現を低下させる化合物を複数得た。得られた化合物の作用機序として、ある転写因子が標的となることが明らかとなった。
化合物の有用性の検証のためパーキンソン病を再現するモデル動物としてalpha -synトランスジェニックマウスに対して酸化ストレスを遺伝的に負荷した新しいモデルマウスの樹立を行った。このマウスでは不溶性のalpha –synが増加している結果を得たことから、孤発性パーキンソン病の一部の病態を反映している可能性が示唆された。

Current Status of Research Progress

Reason

25年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

25年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Design, evaluation and screening methods for efficient targeted mutagenesis with TALENs in medaka. (2014)
  • Author(s): Ansai S, Inohaya K, Yoshiura Y, Schartl M, Uemura N, Takahashi R, Kinoshita M.
  • Journal Title: Dev. Growth Differ. Volume: 56 Pages: 98-107
  • DOI: 10.1111/dgd.12104
  • Peer Reviewed
• [Journal Article] Jan-Feb)XIAP immunoreactivity in glial and neuronal cytoplasmic inclusions in multiple system atrophy.Clin Neuropathol. (2014)
  • Author(s): Kawamoto Y, Ito H, Ihara M, Takahashi R
  • Journal Title: Clin Neuropathol. Volume: 33 Pages: 76-83
  • DOI: 10.5414/NP300610.
  • Peer Reviewed
• [Journal Article] Involvement of Wnt/β-catenin signaling in the development of neuropathic pain. (2014)
  • Author(s): Itokazu T, Hayano Y, Takahashi R, Yamashita T
  • Journal Title: Neurosci Res. Volume: 79 Pages: 34-40
  • DOI: 10.1016/j.neures.2013.12.002.
  • Peer Reviewed
• [Journal Article] Transglutaminase 2 accelerates neuroinflammation in amyotrophic lateral sclerosis through interaction with misfolded superoxide dismutase 1. (2014)
  • Author(s): Oono M, Okado-Matsumoto A, Shodai A, Ido A, Ohta Y, Abe K, Ayaki T, Ito H, Takahashi R, Taniguchi N, Urushitani M
  • Journal Title: J Neurochem. Volume: 128 Pages: 403-418
  • DOI: 10.1111/jnc.12441.
  • Peer Reviewed
• [Journal Article] Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. (2013)
  • Author(s): Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N,Takahashi R, Iwata N, Yamanaka S, Inoue H, et al
  • Journal Title: Cell Stem Cell Volume: 12 Pages: 487-496
  • DOI: 10.1016/j.stem.2013.01.009.
  • Peer Reviewed
• [Journal Article] ATP13A2 deficiency induces a decrease in cathepsin D activity, fingerprint-like inclusion body formation, and selective degeneration of dopaminergic neurons. (2013)
  • Author(s): Matsui H, Sato F, Sato S, Koike M, Taruno Y, Saiki S, Funayama M, Ito H, Taniguchi Y, Uemura N, Toyoda A, Sakaki Y, Takeda S, Uchiyama Y, Hattori N, Takahashi R.
  • Journal Title: FEBS Lett. Volume: 9 Pages: 1316-1325
  • DOI: S0014-5793(13)00192-0. 10.1016/j.febslet.2013.02.046.
  • Peer Reviewed
• [Journal Article] Aberrant assembly of RNA-recognition motif 1 links to pathogenic conversion of TAR DNA-binding protein-43 (TDP-43) (2013)
  • Author(s): Shodai A, Morimura T, Ido A, Uchida T, Ayaki T, Takahashi R, Kitazawa S, Suzuki S, Shirouzu M, Kigawa T, Muto Y, Yokoyama S, Takahashi R, Kitahara R, Ito H, Fujiwara N, Urushitani M
  • Journal Title: J Biol Chem Volume: 288 Pages: 14886-14905
  • DOI: 10.1074/jbc.M113.451849
  • Peer Reviewed
• [Journal Article] Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. (2013)
  • Author(s): Iguchi Y, Katsuno M, Niwa J, Takagi S, Ishigaki S, Ikenaka K, Kawai K, Watanabe H, Yamanaka K, Takahashi R, Misawa H, Sasaki S, Tanaka F, Sobue G.
  • Journal Title: Brain Volume: 136 Pages: 1371-1382
  • DOI: 10.1093/brain/awt029.
  • Peer Reviewed
• [Journal Article] Synthesis and biological evaluation of novel styryl benzimidazole derivatives as probes for imaging of neurofibrillary tangles in Alzheimer's disease. (2013)
  • Author(s): Matsumura K, Ono M, Yoshimura M, Kimura H, Watanabe H, Okamoto Y, Ihara M, Takahashi R, Saji H.
  • Journal Title: Bioorg Med Chem Volume: 21 Pages: 3356-3362
  • DOI: 10.1016/j.bmc.2013.02.054.
  • Peer Reviewed
• [Journal Article] Response to comment on "Drug screening for ALS using patient-specific induced pluripotent stem cells (2013)
  • Author(s): Egawa N, Kitaoka S, Tsukita K, Naitoh M, Takahashi R, Marchetto MC, Gage FH, Yamanaka S, Inoue H, et al
  • Journal Title: Sci Transl Med Volume: 5 Pages: 188lr2
  • DOI: 10.1126/scitranslmed.3005697.
  • Peer Reviewed
• [Journal Article] PINK1 and Parkin complementarily protect dopaminergic neurons in vertebrates. (2013)
  • Author(s): Matsui H, Gavinio R, Asano T, Uemura N, Ito H, Taniguchi Y, Kobayashi Y, Maki T, Shen J, Takeda S, Uemura K, Yamakado H, Takahashi R
  • Journal Title: Hum Mol Genet. Volume: 22 Pages: 2423-2434
  • DOI: 10.1093/hmg/ddt095
  • Peer Reviewed
• [Journal Article] Copper enhances APP dimerization and promotes Aβ production. (2013)
  • Author(s): Noda Y, Asada M, Kubota M, Maesako M, Watanabe K, Uemura M, Kihara T,Shimohama S, Takahashi R, Kinoshita A, Uemura K.
  • Journal Title: Neurosci Lett. Volume: 28 Pages: 10-15
  • DOI: 10.1016/j.neulet.2013.04.057.
  • Peer Reviewed
• [Journal Article] Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice (2013)
  • Author(s): Ageta-Ishihara N, Yamakado H, Morita T, Hattori S, Takao K, Miyakawa T, Takahashi R, Kinoshita M
  • Journal Title: Mol Brain Volume: 6 Pages: 35-35
  • DOI: 10.1186/1756-6606-6-35
  • Peer Reviewed
• [Journal Article] Optineurin suppression causes neuronal cell death via NF-κB pathway. (2013)
  • Author(s): Akizuki M, Yamashita H, Uemura K, Maruyama H, Kawakami H, Ito H, Takahashi R.
  • Journal Title: J Neurochem. Volume: 126 Pages: 699-704
  • DOI: 10.1111/jnc.12326.
  • Peer Reviewed
• [Journal Article] Nardilysin prevents amyloid plaque formation by enhancing α-secretase activity in an Alzheimer's disease mouse model. (2013)
  • Author(s): Ohno M, Hiraoka Y, Lichtenthaler SF, Nishi K, Saijo S, Matsuoka T, Tomimoto H, Araki W, Takahashi R, Kita T, Kimura T, Nishi E.
  • Journal Title: Neurobiol Aging. Volume: 35 Pages: 213-222
  • DOI: 10.1016/j.neurobiolaging.2013.07.014.
  • Peer Reviewed
• [Journal Article] Continuation of Exercise Is Necessary to Inhibit High Fat Diet-Induced β-Amyloid Deposition and Memory Deficit in Amyloid Precursor Protein Transgenic Mice. (2013)
  • Author(s): Maesako M, Uemura K, Iwata A, Kubota M, Watanabe K, Uemura M, Noda Y, Asada-Utsugi M, Kihara T, Takahashi R, Shimohama S, Kinoshita A.
  • Journal Title: PLoS One Volume: 8 Pages: e72796
  • DOI: 10.1371/journal.pone.0072796.
  • Peer Reviewed
• [Journal Article] Protein Disulfide Isomerase P5-Immunopositive Inclusions in Patients with Alzheimer's Disease. (2013)
  • Author(s): Honjo Y, Horibe T, Torisawa A, Ito H, Nakanishi A, Mori H, Komiya T, Takahashi R, Kawakami K.
  • Journal Title: J Alzheimers Dis. Volume: 38 Pages: 601-609
  • DOI: 10.3233/JAD-130632.
  • Peer Reviewed
• [Journal Article] The function of parkin: revisited. (2013)
  • Author(s): Yamakado H, Takahashi R.
  • Journal Title: Mov Disord. Volume: 28 Pages: 1936-1936
  • DOI: 10.1002/mds.25711.
  • Peer Reviewed
• [Journal Article] Genetic correction will be a standard method for the patient-derived ips cell research? (2013)
  • Author(s): Takahashi R, Yamakado H.
  • Journal Title: Mov Disord. Volume: 28 Pages: 1935-1935
  • DOI: 10.1002/mds.25710.
  • Peer Reviewed
• [Journal Article] Development of Novel (123)I-Labeled Pyridyl Benzofuran Derivatives for SPECT Imaging of β-Amyloid Plaques in Alzheimer's Disease. (2013)
  • Author(s): Ono M, Cheng Y, Kimura H, Watanabe H, Matsumura K, Yoshimura M, Iikuni S, Okamoto Y, Ihara M, Takahashi R, Saji H.
  • Journal Title: PLoS One Volume: 8 Pages: e74104
  • DOI: 10.1371/journal.pone.0074104.
  • Peer Reviewed
• [Journal Article] Chicken DT40 cell line lacking DJ-1, the gene responsible for familial Parkinson's disease, displays mitochondrial dysfunction. (2013)
  • Author(s): Minakawa EN, Yamakado H, Tanaka A, Uemura K, Takeda S, Takahashi R.
  • Journal Title: Neurosci Res. Volume: 77 Pages: 228-233
  • DOI: S0168-0102(13)00203-4. 10.1016/j.neures.2013.09.006.
  • Peer Reviewed
• [Journal Article] Exploring the Pathogenetic Mechanisms underlying Parkinson's Disease in Medaka Fish. (2013)
  • Author(s): Matsui H, Uemura N, Yamakado H, Takeda S, Takahashi R
  • Journal Title: J Parkinsons Dis. Volume: Epub ahead of print
  • Peer Reviewed
• [Journal Article] Tricornered/NDR kinase signaling mediates PINK1-directed mitochondrial quality control and tissue maintenance. (2013)
  • Author(s): Wu Z, Sawada T, Shiba K, Liu S, Kanao T, Takahashi R, Hattori N, Imai Y, Lu B
  • Journal Title: Genes Dev. Volume: 27 Pages: 157-162
  • DOI: 10.1101/gad.203406.112.
  • Peer Reviewed
• [Presentation] Fish model of Parkinson's disease (2013)
  • Author(s): Ryosuke Takahashi
  • Organizer: Swiss-Kyoto Symposium
  • Place of Presentation: Kyoto
  • Year and Date: 20131121-20131122
  • Invited
• [Presentation] Viable Gaucher's disease model of medaka fish completely deficienct in glucocerebrosidase activity developed alpha-synuclein aggregation in the brain. (2013)
  • Author(s): Norihito Uemura, Tomoko Fujiwara-Ishikawa, Masato Kinoshita, Masato Koike, Hideaki Matsui, Hodaka Yamakado, Kengo Uemura, Yasuo Uchiyama, Takeshi Todo, Shun-ichi Takeda, Ryosuke Takahashi.
  • Organizer: Neuroscience 2013
  • Place of Presentation: SanDiego
  • Year and Date: 20131109-20131113
• [Presentation] Exploring the molecular mechanism underlying Parkinson's diease with genetic medaka models. (2013)
  • Author(s): Ryosuke Takahashi
  • Organizer: International Symposium on Mitochondria 2013
  • Place of Presentation: Tokyo
  • Year and Date: 20131106-20131106
  • Invited
• [Presentation] α-Synucleinの発現量の調節を標的とするパーキンソン病治療薬剤のスクリーニング (2013)
  • Author(s): 浅野剛史、山門穂高、高橋良輔
  • Organizer: 第36回日本神経科学大会
  • Place of Presentation: 京都
  • Year and Date: 20130620-20130623
• [Presentation] Parkinson's disease by modifying α-synuclein expression. (2013)
  • Author(s): Hodaka Yamakado, Takeshi Asano, Ryosuke Takahashi
  • Organizer: The MDS 17th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: Sydney
  • Year and Date: 20130616-20130620
• [Presentation] PINK1とParkinは脊椎動物において相補的にミトコンドリアを保護する (2013)
  • Author(s): 浅野剛史, 松井秀彰, Robert Gavinio, 上村紀人, 伊東秀文, 谷口 善仁, Jie Shen, 武田俊一, 植村健吾, 山門穂高, 高橋良輔
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸
  • Year and Date: 2013-12-14
• [Book] 細胞死研究の今-疾患との関わり、創薬に,創薬に向けてのアプローチ- (2013)
  • Author(s): 守村敏史，高橋良輔，漆谷 真
  • Total Pages: 8
  • Publisher: メディカルドゥ
• [Remarks] 京都大学医学研究科臨床神経学
  • URL: http://www.kuhp.kyoto-u.ac.jp/~neurology/