Drug development for polyglutamine diseases by a combined phenotype analysis system

2011 Fiscal Year Final Research Report

• Project/Area Number: 21390265
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• 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)
• Research Collaborator: 田川 一彦 ; 田村 拓也 ; 戚 美玲 ; 伊藤 日加瑠 ; 塩飽 裕紀 ; 榎戸 靖 ; 曽根 雅紀
• Project Period (FY): 2009 – 2011
• Keywords: 神経分子病態学 / ポリグルタミン病 / ハイスループット

Research Abstract

We developed strategically a combined model system for analyzing phenotypes and pathomechanisms and available for developing novel therapeutics of polyglutamine diseases. The system consisted of cell, fly and mouse models was very powerful when combined with omics analyses. We could elucidate a new pathomechanism of polyglutamine diseases, DNA repair impairment and could identify key molecules such as HMGB, Ku70, Hsp70, Omi and Maxer. Furthermore, we identified candidate drugs for polyglutamine diseases by using the combined analysis system.

Research Products

• [Journal Article] Ataxin-7 associates with microtubules and stabilizes the cytoskeletal network (2012)
  • Author(s): Nakamura, Y., Tagawa, K., Oka, T., Sasabe, T., Ito, H., Shiwaku, H., La Spada, A. R. and Okazawa, H
  • Journal Title: Hum Mol Genet Volume: 21(5) Pages: 1099-1110
  • DOI: doi:10.1093/hmg/ddr539
  • Peer Reviewed
• [Journal Article] The solution model of the intrinsically disordered polyglutamine tract binding protein-1(PQBP-1) (2012)
  • Author(s): Ress, M., Gorba, C., Gorba, C., de Chiara, C., Bui, T. T. T., Garcia-Maya, M., Drake, A. F., Okazawa, H., Pastre, A., Svergun, D. and Chen, Y. W
  • Journal Title: Biophys J Volume: (in press)
• [Journal Article] Dynamic Changes of the Phosphoproteome in Postmortem Mouse Brains (2011)
  • Author(s): Oka, T., Tagawa, K., Ito, H. and Okazawa, H
  • Journal Title: PLoS One Volume: 6 Pages: e21405
  • DOI: doi:10.1371/journal.pone.0021405
  • Peer Reviewed
• [Journal Article] Ku70 alleviates neurodegeneration in Drosophila models of Huntington's disease (2011)
  • Author(s): Tamura, T., Sone, M., Iwatsubo, T., Tagawa, K., Wanker, E. E. and Okazawa, H
  • Journal Title: PLoS One Volume: 6 Pages: e27408
  • DOI: doi:10.1371/journal.pone.0027408
  • Peer Reviewed
• [Journal Article] Mutant huntingtin impairs Ku70-mediated DNA repair (2010)
  • Author(s): Enokido, Y., Tamura, T., Ito, H., Arumughan, A., Komuro, A., Shiwaku, H., Sone, M., Foulle, R., Sawada, H., Ishiguro, H., Ono, T., Murata, M., Kanazawa, I., Tomilin, N., Tagawa, K., Wanker, E. E., and Okazawa, H.
  • Journal Title: J CellBiol Volume: 189 Pages: 425-443
  • DOI: doi:10.1083/jcb.200905138
  • Peer Reviewed
• [Journal Article] Polyglutamine tract-binding protein-1 binds to U5-15kD via a continuous 23-residue segment of the C-terminal domain (2010)
  • Author(s): Takahashi, M., Mizuguchi, M., Shinoda, H., Aizawa, T., Demura, M., Okazawa, H., and Kawano, K.
  • Journal Title: Biochim Biophys Acta Volume: 1804 Pages: 1500-1507
  • DOI: doi:10.1016/j.bbapap.2010.03.007
  • Peer Reviewed
• [Journal Article] Suppression of the novel ER protein Maxer by mutant ataxin-1 in Bergman glia contributes to non-cell-autonomous toxicity (2010)
  • Author(s): Shiwaku, H., Yoshimura, N., Tamura, T., Sone, M., Ogishima, S., Watase, K., Tagawa, K., and Okazawa, H.
  • Journal Title: EMBO J. Volume: 29 Pages: 2446-2460
  • DOI: doi:10.1038/emboj.2010.116
  • Peer Reviewed
• [Journal Article] Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis (2010)
  • Author(s): Honda, S., Hayashi, S., Imoto, I., Toyama, J., Okazawa, H., Nakagawa, E., Goto, Y., and Inazawa, J.
  • Journal Title: J Hum Genet Volume: 55 Pages: 590-599
  • DOI: doi:10.1038/jhg.2010.74
  • Peer Reviewed
• [Journal Article] Efficiently differentiating vascular endothelial cells from adipose tissue-derived mesenchymal stem cells in serum-freeculture (2010)
  • Author(s): Konno, M., Hamazaki, T. S., Fukuda, S., Tokuhara, M., Uchiyama, H., Okazawa, H., Okochi, H., and Asashima, M.
  • Journal Title: Biochem Biophys Res Commun Volume: 400 Pages: 461-465
  • DOI: doi:10.1016/j.bbrc.2010.08.029
  • Peer Reviewed
• [Journal Article] Drosophila PQBP1 regulates learning acquisition at projection neurons in aversive olfactory conditioning (2010)
  • Author(s): Tamura, T., Horiuchi, D., Chen, Y. C., Sone, M., Miyashita, T., Saitoe, M., Yoshimura, N., Chiang, A. S., and Okazawa, H.
  • Journal Title: J Neurosci Volume: 30 Pages: 14091-14101
  • DOI: doi:10.1523/JNEUROSCI.1319-10.
• [Journal Article] In-frame Dystrophin Following Exon 51-Skipping Improves Muscle Pathology and Function in the Exon 52-Deficient mdx Mouse (2010)
  • Author(s): Aoki, Y., Nakamura, A., Yokota, T., Saito, T., Okazawa, H., Nagata, T., and Takeda, S
  • Journal Title: Mol Ther Volume: 18 Pages: 1995-200
  • Peer Reviewed
• [Journal Article] Nematode homologue of PQBP1, a mental retardation causative gene, is involved in lipid metabolism (2009)
  • Author(s): Takahashi, K., Yoshina, S., Masashi, M., Ito, W., Inoue, T., Shiwaku, H., Arai, H., Mitani, S., and Okazawa, H.
  • Journal Title: PLoS One Volume: 4 Pages: e4104
  • DOI: doi:10.1371/journal.pone.0004104.
  • Peer Reviewed
• [Journal Article] Glial cell lineage expression of mutant ataxin-1 and huntingtin induces developmental and late-onset neuronal pathologies in Drosophila models (2009)
  • Author(s): Tamura, T., Sone, M., Yamashita, M., Wanker, E. E., and Okazawa, H.
  • Journal Title: PLoS One Volume: 4 Pages: e4262
  • DOI: doi:10.1371/journal.pone.0004262
  • Peer Reviewed
• [Journal Article] Loss of yata, a novel gene regulating the subcellular localization of APPL, induces deterioration of neural tissues and lifespan shortening (2009)
  • Author(s): Sone, M., Uchida, A., Komatsu, A., Suzuki, E., Ibuki, I., Asada, M., Shiwaku, H., Tamura, T., Hoshino, M., Okazawa, H., and Nabeshima, Y.
  • Journal Title: PLoS One Volume: 4 Pages: e4466
  • DOI: doi:10.1371/journal.pone.0004466
  • Peer Reviewed
• [Journal Article] Progressive decrease in the level of YAPdeltaCs, prosurvival isoforms of YAP, in the spinal cord of transgenic mouse carrying a mutant SOD1 gene (2009)
  • Author(s): Morimoto, N., Nagai, M., Miyazaki, K., Kurata, T., Takehisa, Y., Ikeda, Y., Kamiya, T., Okazawa, H., and Abe, K.
  • Journal Title: J Neurosci Res Volume: 87 Pages: 928-936
  • DOI: doi:10.1002/jnr.21902
  • Peer Reviewed
• [Journal Article] Polyglutamine tract binding protein-1 is an intrinsically unstructured protein (2009)
  • Author(s): Takahashi, M., Mizuguchi, M., Shinoda, H., Aizawa, T., Demura, M., Okazawa, H., and Kawano, K.
  • Journal Title: Biochim Biophys Acta Volume: 1794 Pages: 936-943
  • DOI: doi:10.1016/j.bbapap.2009.03.001
  • Peer Reviewed
• [Journal Article] Neural stem cells express Oct-3/4 (2009)
  • Author(s): Chin, J. H., Shiwaku, H., Goda, O., Komuro, A., and Okazawa, H.
  • Journal Title: Biochem Biophys Res Commun Volume: 388 Pages: 247-251
  • DOI: doi:10.1016/j.bbrc.2009.07.165
  • Peer Reviewed
• [Journal Article] Knock-down of PQBP1 impairs anxiety-related cognition in mouse (2009)
  • Author(s): Ito, H., Yoshimura, N., Kurosawa, M., Ishii, S., Nukina, N., and Okazawa, H.
  • Journal Title: Hum Mol Genet Volume: 18 Pages: 4239-4254
  • DOI: doi:10.1093/hmg/ddp378
  • Peer Reviewed
• [Journal Article] Omi/HtrA2 is relevant to the selective vulnerability of striatal neurons in Huntington's disease (2008)
  • Author(s): Inagaki, R., Tagawa, K., Qi, M. L., Enokido, Y., Ito, H., Tamura, T., Shimizu, S., Oyanagi, K., Arai, N., Kanazawa, I., Wanker E. E, and Okazawa, H.
  • Journal Title: Eur J Neurosci Volume: 28 Pages: 30-40
  • DOI: doi:10.1111/j.1460-9568.2008.06323.x
  • Peer Reviewed
• [Journal Article] Age-dependent change of HMGB1 and DNA double-strand break accumulation in mouse brain (2008)
  • Author(s): Enokido, Y., Yoshitake, A., Ito, H., and Okazawa, H.
  • Journal Title: Biochem Biophys Res Commun Volume: 376 Pages: 128-133
  • DOI: doi:10.1016/j.bbrc.2008.08.108
  • Peer Reviewed
• [Journal Article] The induction levels of heat shock protein 70 differentiate the vulnerabilities to mutant huntingtin among neuronal subtypes (2007)
  • Author(s): Tagawa, K., Marubuchi, S., Qi, M. L., Enokido, Y., Tamura, T., Inagaki, R., Murata, M., Kanazawa, I., Wanker, E. E., and Okazawa, H.
  • Journal Title: J Neurosci Volume: 27 Pages: 868-880
  • DOI: doi:10.1523/JNEUROSCI.4522-06.200
  • Peer Reviewed
• [Journal Article] Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases (2007)
  • Author(s): Qi, M. L., Tagawa, K., Enokido, Y., Yoshimura, N., Wada, Y., Watase, K., Ishiura, S., Kanazawa, I., Botas, J., Saitoe, M., Wanker, E. E., and Okazawa, H.
  • Journal Title: Nature Cell Biol Volume: 9 Pages: 402-414
  • DOI: doi:10.1523/JNEUROSCI.4522-06.200
  • Peer Reviewed
• [Presentation] PQBP1 a new major causative gene for mental retardation and microcephaly, regulates gene expression through mRNA splicing. Elsevier Conference (2011)
  • Author(s): Okazawa, H
  • Organizer: RNA Binding Proteins in Neurological Disease, Sheraton National
  • Place of Presentation: Arlington, U. S. A
  • Year and Date: 20111110-11
• [Presentation] Molecular Mechanisms of PQBP1-Linked MR and Microcephaly (2011)
  • Author(s): Okazawa, H
  • Organizer: 15th International Workshop on Fragile X and Other Early-Onset Cognitive Disorders, Harnack-House
  • Place of Presentation: Berlin, Germany
  • Year and Date: 20110904-07
• [Presentation] PQBP1 controls brain size through cell cycle regulation of neural stem cells (2008)
  • Author(s): Luo, H., Okazawa, H
  • Organizer: Days of Molecular Medicine 2008, Karolinska Institutet
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 20080417-19
• [Presentation] Proteome analysis of soluble nuclear proteins unravels a novel cell-protective role of HMGB1/2 to suppress genotoxic stress in the polyglutamine disease pathology (2007)
  • Author(s): Okazawa, H., Qi, M. L
  • Organizer: III Meeting on the Molecular Mechanisms of Neurodegeneration
  • Place of Presentation: Milano, Italy
  • Year and Date: 20070519-21
• [Presentation] Proteome analysis of soluble nuclear proteins unravels a novel cell-protective role of HMGB1/2 to suppress genotoxic stress in the polyglutamine disease pathology (2007)
  • Author(s): Okazawa, H., Qi, M. L
  • Organizer: Gordon Research Conferences 2007 Meeting, CAG Triplet Repeat Disorders, Centre Paul Langevin
  • Place of Presentation: Aussois, France
  • Year and Date: 20070513-18
• [Book] POLYGLUTAMINEDISEASES in Handbook of Neurochemistry and Molecular Neurobiology : Neural Protein Metabolism and Function
  • Author(s): Okazawa, H.
  • Publisher: Edited by A Lajtha, Springer
• [Remarks] 2007. 3. 26「東京医科歯科大、神経変性疾患、関連タンパク特定-治療法開発も」日本経済産業新聞
• [Remarks] 2007. 3. 26「東京医科歯科大、JST、HMGBたんぱく質が神経細胞を正常な状態に保つ作用を発見」日経Biotechnology Japan
• [Remarks] 2007. 4. 2「DNA修復タンパクが減少難病の治療につながる可能性」共同通信
• [Remarks] 2007. 4. 2「DNA修復タンパクが減少難病の神経変性疾患で」東京新聞
• [Remarks] 2007. 4. 2「DNA修復タンパクが減少難病の神経変性疾患で」京都新聞
• [Remarks] 2010. 4. 28プレスリリース「ハンチントン病の主要病態がDNA損傷修復障害による神経変性であることを解明」? DNA修復機能回復によるハンチントン病の新たな治療法の開発-
• [Remarks] 2010. 5. 4「DNA修復障害が原因ハンチントン病マウス実験で確認」産経新聞朝刊20面
• [Remarks] 2010. 5. 4「神経の難病『ハンチントン病』原因の一端解明医科歯科大など」日本経済新聞朝刊26面
• [Remarks] 2010. 5. 4「ハンチントン病損傷DNA修復を阻害東京医科歯科大教授ら原因たんぱく質解明」毎日新聞朝刊2面
• [Remarks] 2010. 5. 4「ハンチントン病はDNA修復障害東京医科歯科大教授ら発表」共同通信
• [Remarks] 2010. 5. 4「神経難病の原因解明」東京新聞3面
• [Remarks] 2010. 5. 4「原因はDNA修復障害ハンチントン病新たな治療法へ道岡澤教授(東京医科歯科大)ら米誌発表」東奥日報朝刊15面
• [Remarks] 2010. 5. 4「ハンチントン病DNA修復障害が原因」山形新聞朝刊19面
• [Remarks] 2010. 5. 4「神経難病『ハンチントン病』DNA修復障害が原因」茨城新聞朝刊17面
• [Remarks] 2010. 5. 4「DNAの修復阻害ハンチントン病病態を解明東京医歯大教授ら」静岡新聞朝刊21面
• [Remarks] 2010. 5. 4「ハンチントン病の原因DNA修復機能せず東京医科歯科大教授ら発表」信濃毎日新聞朝刊22面
• [Remarks] 2010. 5. 4「神経難病『ハンチントン病』原因タンパク質DNA修復障害東京医歯大教授ら確認」愛媛新聞朝刊3面
• [Remarks] 2010. 5. 4「神経難病ハンチントン病DNA修復障害原因東京医歯大教授ら発表」宮崎日日新聞朝刊5面
• [Remarks] 2010. 5. 4「神経難病ハンチントン病DNA修復障害が原因」大分合同新聞朝刊3面
• [Remarks] 2010. 5. 7「ハンチントン病の発症にDNA修復蛋白Ku70が関与東京医科歯科大グループが発表、治療法の開発に光明か」メディカルトリビューン
• [Remarks] 2010. 5. 7「ハンチントン病原因解明東京医科歯科大DNA修復の酵素不足」読売新聞夕刊16面
• [Remarks] 2010. 5. 21「ハンチントン病の発症解明」朝日新聞25面
• [Remarks] 2010. 6. 8 プレスリリース（JST と共同） 「小脳変性に関与する分子メカニズムを解明（神経変性疾患の治療開発につながることが期待）」
• [Remarks] 2010. 6. 9「小脳の神経細胞変性分子メカニズム解明東京医科歯科大」日刊工業21面
• [Remarks] 2010. 6. 25「「1リットルの涙」難病の原因に迫る」朝日新聞朝刊33面
• [Remarks] 2010. 10. 20「東京医科歯科大学、NMDA受容体のNR1サブユニットの減少がポリグルタミン病による認知障害に関連」BTJアカデミック
• [Patent(Industrial Property Rights)] Prophylactic/Therapeutic Agent for Neurodegenerative Disease (2010)
  • Inventor(s): Hitoshi Okazawa
  • Industrial Property Rights Holder: National Corporation Tokyo Medical and Dental University
  • Industrial Property Number: Application Number:12/313,837, Patent Number: 7833975
  • Filing Date: 2010-09-17
  • Acquisition Date: 2010-11-16
  • Overseas
• [Patent(Industrial Property Rights)] Prophylactic/Therapeutic Agent for Neurodegenerative Disease (2007)
  • Inventor(s): Hitoshi Okazawa
  • Industrial Property Rights Holder: National Corporation Tokyo Medical and Dental University
  • Industrial Property Number: Application Number:07742308.5, Patent Number:2039367
  • Filing Date: 2007-04-24
  • Acquisition Date: 2007-04-27
  • Overseas
• [Patent(Industrial Property Rights)] Gene Encoding a Protein and Preventive/Remedy for Neurodegenerative Diseases such as Polyglutamine Diseases by Utilizing the Same (2005)
  • Inventor(s): Hitoshi Okazawa
  • Industrial Property Rights Holder: National Corporation Tokyo Medical and Dental University
  • Industrial Property Number: Application Number:11/791,053, Patent Number:7951928
  • Filing Date: 2005-11-16
  • Acquisition Date: 2011-05-31
  • Overseas
• [Patent(Industrial Property Rights)] Novel Protein and Preventive/Remedy for Neurodegenerative Disease such as Polyglutamine Disease Using the Same (2005)
  • Inventor(s): Hitoshi Okazawa
  • Industrial Property Rights Holder: National Corporation Tokyo Medical and Dental University
  • Industrial Property Number: Application Number:05807046.7, Patent Number:1878793
  • Filing Date: 2005-11-16
  • Acquisition Date: 2011-08-24
  • Overseas