Therapeutics development against intellectual disability via structural biology analyses

• Project/Area Number: 26640037
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Okazawa Hitoshi 東京医科歯科大学, 難治疾患研究所, 教授 (50261996)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: PQBP1 / スプライシング異常 / 構造生物学 / 遺伝子治療 / 小頭症 / 知的障害 / 神経変性疾患 / 神経変性 / 発達障害 / スプライシング / AIDS / HIV / 冠動脈疾患 / 天然変性タンパク質 / RNA / 機能障害

Outline of Final Research Achievements

RNA splicing is implicated in the molecular pathology of neurological diseases, and the concept of RNA splicing diseases has been proposed. In this project, we focused on PQBP1, which is a representative RNA splicing disease gene, a representative disease gene of intellectual disability (ID), and a neurodegeneration-related gene. We intended to perform structural biology analysis of PQBP1 and develop revolutional therapy. As the results, we elucidated pathomechanisms of PQBP1-linked ID/microcephaly through splicing impairment, developed a gene therapy against this disorder. We also clarified structural basis of nteraction between PQBP1 and U5-15KD.

Research Products

• [Journal Article] 神経疾患におけるリン酸化シグナルの網羅的解析 (2016)
  • Author(s): 田川 一彦、本間 秀典、岡澤 均
  • Journal Title: Clinical Neuroscience. Volume: 34 Pages: 119-120
• [Journal Article] Quantitative Histological Validation of Diffusion Tensor MRI with Two-Photon Microscopy of Cleared Mouse Brain (2016)
  • Author(s): Kamagata, K., Kerever, A., Yokosawa, S., Otake, Y., Ochi, H., Hori, M., Kamiya, K., Tsuruta, K., Tagawa, K., Okazawa, H., Aoki, S., Arikawa-Hirasawa, E.
  • Journal Title: Magnetic Resonance in Medical Sciences Volume: 15 Issue: 4 Pages: 416-421
  • DOI: 10.2463/mrms.bc.2015-0148
  • NAID: 130005421023
  • ISSN: 1347-3182, 1880-2206
  • Peer Reviewed / Open Access
• [Journal Article] Fasting activates macroautophagy in neurons of Alzheimer's disease mouse model but is insufficient to degrade amyloid-beta. (2015)
  • Author(s): Chen, X., Kondo, K., Motoki, K., Homma, H., Okazawa H.
  • Journal Title: Scientific Reports. Volume: 5 Issue: 1
  • DOI: 10.1038/srep12115
  • Peer Reviewed / Open Access
• [Journal Article] Impaired DNA damage repair as a common feature of neurodegenerative diseases and psychiatric disorders. (2015)
  • Author(s): Shiwaku H, Okazawa H.
  • Journal Title: Curr Mol Med. Volume: 15 Pages: 119-28
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Comprehensive phosphoproteome analysis unravels the core signaling network that initiates the earliest synapse pathology in preclinical Alzheimer's disease brain. (2015)
  • Author(s): Tagawa K, Homma H, Saito A, Fujita K, Chen X, Imoto S, Oka T, Ito H, Motoki K, Yoshida C, Hatsuta H, Murayama S, Iwatsubo T, Miyano S, Okazawa H.
  • Journal Title: Hum Mol Genet. Volume: 24 Issue: 2 Pages: 540-58
  • DOI: 10.1093/hmg/ddu475
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells. (2015)
  • Author(s): Ito H, Shiwaku H, Yoshida C, Homma H, Luo H, Chen X, Fujita K, Musante L, Fischer U, Frints SG, Romano C, Ikeuchi Y, Shimamura T, Imoto S, Miyano S, Muramatsu SI, Kawauchi T, Hoshino M, Sudol M, Arumughan A, Wanker EE, Rich T, Schwartz C, Matsuzaki F, Bonni A, Kalscheuer VM, Okazawa H.
  • Journal Title: Mol Psychiatry Volume: 20 Issue: 4 Pages: 459-71
  • DOI: 10.1038/mp.2014.69
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Systematic analysis of fly models with multiple drivers reveals different effects of Ataxin-1 and Huntingtin in neuron subtype-specific expression. (2014)
  • Author(s): Risa Shiraishi, Takuya Tamura, Masaki Sone, Hitoshi Okazawa
  • Journal Title: PLoS One Volume: 9 Issue: 12 Pages: e116567-e116567
  • DOI: 10.1371/journal.pone.0116567
  • Peer Reviewed / Open Access
• [Journal Article] HMGB1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin-1 knock-in mice. (2014)
  • Author(s): Ito H, Fujita K, Tagawa K, Chen X, Homma H, Sasabe T, Shimizu J, Shimizu S, Tamura T, Muramatsu S, Okazawa H.
  • Journal Title: EMBO Mol Med. Volume: 7 Issue: 1 Pages: 78-101
  • DOI: 10.15252/emmm.201404392
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Segmental isotope-labeling of the intrinsically disordered protein PQBP1. (2014)
  • Author(s): Nabeshima Y, Mizuguchi M, Kajiyama A, Okazawa H.
  • Journal Title: FEBS Lett. Volume: 588 Issue: 24 Pages: 4583-9
  • DOI: 10.1016/j.febslet.2014.10.028
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mutations in the gene PQBP1 prevent its interaction with the spliceosomal protein U5-15kD (2014)
  • Author(s): Mizuguchi, M., Obita, T., Serita, T., Kojima, R., Nabeshima, Y., and Okazawa, H.
  • Journal Title: Nat Commun. Volume: 5 Issue: 1 Pages: 3822-3822
  • DOI: 10.1038/ncomms4822
  • Peer Reviewed
• [Presentation] 「早期アルツハイマー病モデルマウス脳における網羅的リン酸化プロテオーム解析」 (2015)
  • Author(s): 田川 一彦、本間 秀典、斉藤 あゆむ、藤田 慶大、陳 西貴、村山 繁雄、岩坪 威、宮野 悟、岡澤 均
  • Organizer: 第34回日本認知症学会学術集会
  • Place of Presentation: リンクステーションホール青森/ホテル青森（青森県青森市）
  • Year and Date: 2015-10-02
• [Presentation] 「早期アルツハイマー病脳における網羅的リン酸化プロテオーム解析」 (2015)
  • Author(s): 田川 一彦、本間 秀典、斉藤 あゆむ、村山 繁雄、岩坪 威、宮野 悟、岡澤 均
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 第38回日本神経科学大会
  • Year and Date: 2015-07-30
• [Presentation] 「早期アルツハイマー病脳における網羅的リン酸化プロテオーム解析」 (2015)
  • Author(s): 田川 一彦、本間 秀典、斉藤 あゆむ、村山 繁雄、岩坪 威、宮野 悟、岡澤 均
  • Organizer: 第56回日本神経病理学会総会学術研究会
  • Place of Presentation: 九州大学医学部百年講堂（福岡県福岡市）
  • Year and Date: 2015-06-04
• [Presentation] HMGB1 gene therapy ameliorates phenotype of mutant ataxin-1 knock-in mice (2015)
  • Author(s): 伊藤 日加瑠、藤田 慶大、田川 一彦、陳 西貴、本間 秀典、笹邊 俊和、清水 潤、清水 重臣、村松 慎一、岡澤 均
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ（新潟コンベンションセンター）/ホテル日航新潟（新潟県新潟市）
  • Year and Date: 2015-05-21
• [Presentation] Comprehensive phosphoproteome analysis in preclinical Alzheimer's disease brain (2015)
  • Author(s): 田川 一彦、本間 秀典、斉藤 あゆむ、村山 繁雄、岩坪 威、宮野 悟、岡澤 均
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ（新潟コンベンションセンター）/ホテル日航新潟（新潟県新潟市）
  • Year and Date: 2015-05-21
• [Presentation] In utero treatment for PQBP-1 gene mutations (2015)
  • Author(s): Hitoshi Okazawa
  • Organizer: 10th International Meeting on Copy Number Variants and Genes in Intellectual Disability and Autism.
  • Place of Presentation: La Cittadella dell'Oasi (Troina, Italy)
  • Year and Date: 2015-04-16
  • Int'l Joint Research / Invited
• [Presentation] シナプス病態から脳疾患治療へ、網羅的質量分析の示唆するアルツハイマー病のシナプス超早期病態の分子機構 (2014)
  • Author(s): 岡澤 均
  • Organizer: 包括脳ネットワーク』冬のシンポジウム「精神神経疾患研究の現状と展望：新学術５領域の相互理解･連携を目指して」
  • Place of Presentation: 東京
  • Year and Date: 2014-12-11
  • Invited
• [Presentation] ゲノム安定性と脳機能 (2014)
  • Author(s): 岡澤 均
  • Organizer: 第37回日本分子生物学会年会 シンポジウム・ゲノム再生
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25 – 2014-11-27
  • Invited
• [Presentation] Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1 (2014)
  • Author(s): Tamura, T., Barclay, S, S., Fujita, K., Ito, H., Motoki, K., Shimamura, T., Tagawa, K., Katsuta, A., Shiwaku, H., Sone, M., Tagawa, K., Imoto, S., Miyano, S., Okazawa, H.
  • Organizer: Neuroscience2014
  • Place of Presentation: Yokohama
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases. (2014)
  • Author(s): Fujita, K., Nakamura, Y., Oka, T., Ito, H., Tamura, T., Tagawa, K., Sasabe, T., Katsuta, A., Motoki, K., Shiwaku, H., Yoshida, C., Sone, M., Okazawa, H.
  • Organizer: Neuroscience2014
  • Place of Presentation: Yokohama
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Comprehensive Phosphoproteome Analysis Unravels the Core Signaling Network that Initiates the Earliest Synapse Pathology in Preclinical Alzheimer’s Disease Brain (2014)
  • Author(s): Okazawa, H.
  • Organizer: ISP Symposium 2014
  • Place of Presentation: Tokyo
  • Year and Date: 2014-08-28
  • Invited
• [Patent(Industrial Property Rights)] 神経幹細胞の増殖の促進に用いられる製剤、神経幹細胞の減少に関連する疾患の予防又は治療に用いられる製剤、シナプス後部形成の促進に用いられる製剤、シナプス後部形成の..（以下正式名称備考欄に記載） (2015)
  • Inventor(s): 岡澤均
  • Industrial Property Rights Holder: 国立大学法人東京医科歯科大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-07-01
  • Overseas
• [Patent(Industrial Property Rights)] 脊髄小脳変性症を予防または治療するための薬剤 (2014)
  • Inventor(s): 岡澤 均
  • Industrial Property Rights Holder: 岡澤 均
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-10-10
• [Patent(Industrial Property Rights)] アルツハイマー病及び前頭側頭葉変性症の診断方法、診断薬、治療薬及びこれらの薬剤スクリーニング法 (2014)
  • Inventor(s): 岡澤 均
  • Industrial Property Rights Holder: 岡澤 均
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-12-25