Study on the mechanism of aggregate formation in neurodegeneration

• Project/Area Number: 17025044
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: NUKINA Nobuyuki The Institute of Physical and Chemical Research, 構造神経病理研究チーム, チームリーダー (10134595)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥115,000,000 (Direct Cost: ¥115,000,000); Fiscal Year 2009: ¥22,500,000 (Direct Cost: ¥22,500,000); Fiscal Year 2008: ¥22,500,000 (Direct Cost: ¥22,500,000); Fiscal Year 2007: ¥22,500,000 (Direct Cost: ¥22,500,000); Fiscal Year 2006: ¥22,500,000 (Direct Cost: ¥22,500,000); Fiscal Year 2005: ¥25,000,000 (Direct Cost: ¥25,000,000)
• Keywords: 分子神経病理学 / 神経変性疾患 / ポリグルタミン病 / 凝集体結合蛋白質 / シャペロン / プロテアソーム / ハンチントン病 / ポリグルタミン / 凝集体 / 凝集体結合蛋白 / ナトリウムチャネルβ4サブユニット / 転写調節障害 / RNA結合蛋白 / クロスシード / 転写因子 / ショウジョウバエ / RNAi / beta4 subunit

Research Abstract

We have been working about the aggregate formation and its effect on the neurodegeneration of polyglutamine diseases in this project, mainly focusing on the identification of the aggregate interacting proteins and of the target molecules for drugs modulating aggregate formation. We could find several molecules, which modulate aggregate formation or its degradation. Our approach is important for developing new therapies in future. Furthermore, we could develop a new gene therapy, in which abnormal disease protein could be specifically degraded. The effect of this treatment in vivo itself revealed the pathological significance of aggregates in the disease process.

Research Products

• [Journal Article] Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein. (2010)
  • Author(s): Bauer, P.O., Goswami, A., Wong, H.K., Okuno, M., Kurosawa, M., Yamada, M., Miyazaki, H., Matsumoto, G., Kino, Y., Nagai, Y., Nukina, N.
  • Journal Title: Nat. Biotechnol. 28 Pages: 256-263
  • Peer Reviewed
• [Journal Article] Mutant huntingtin fragment selectively suppresses Brn-2 POU domain transcription factor to mediate hypothalamic cell dysfunction. (2010)
  • Author(s): Yamanaka, T., Tosaki, A., Miyazaki, H., Kurosawa, M., Furukawa, Y., Yamada, M., Nukina, N.
  • Journal Title: Hum. Mol. Genet. (in press)
  • Peer Reviewed
• [Journal Article] RNAi screening in Drosophila cells identifies new modifiers of mutant huntingtin aggregation. (2009)
  • Author(s): Doumanis, J., Wada, K., Kino, Y., Moore, A.W., Nukina, N.
  • Journal Title: PLoS One 4
  • Peer Reviewed
• [Journal Article] Cross-seeding fibrillation of Q/N-rich proteins offers new pathomechanism of polyglutamine diseases. (2009)
  • Author(s): Furukawa, Y., Kaneko, K., Matsumoto, G., Kurosawa, M., Nukina, N.
  • Journal Title: J. Neurosci. 29 Pages: 5153-5162
  • Peer Reviewed
• [Journal Article] Inhibition of rho kinases enhances the degradation of mutant huntingtin. (2009)
  • Author(s): Bauer, P.O., Wong, H.K., Oyama, F., Goswami, A., Okuno, M., Kino, Y., Miyazaki, H., Nukina, N.
  • Journal Title: J. Biol. Chem. 284 Pages: 13153-13164
  • Peer Reviewed
• [Journal Article] Cross-seeding fibrillation of Q/N-rich proteins offers new pathomechanism of polyglutamine diseases (2009)
  • Author(s): Furukawa, Y.et al.
  • Journal Title: J.Neurosci. 29 Pages: 5153-5162
  • Peer Reviewed
• [Journal Article] Inhibition of rho kinases enhances the degradation of mutant huntingtin (2009)
  • Author(s): Bauer, P.O.et al.
  • Journal Title: J.Biol.Chem. 284 Pages: 13153-13164
  • Peer Reviewed
• [Journal Article] Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism. (2008)
  • Author(s): Wong, H.K., Bauer, P.O., Kurosawa, M., Goswami, A., Washizu, C., Machida, Y., Tosaki, A., Yamada, M., Knopfel, T., Nakamura, T., Nukina, N.
  • Journal Title: Hum. Mol. Genet. 17 Pages: 3223-3235
  • Peer Reviewed
• [Journal Article] Mutant Huntingtin reduces HSP70 expression through the sequestration of NF-Y transcription factor. (2008)
  • Author(s): Yamanaka, T., Miyazaki, H., Oyama, F., Kurosawa, M., Washizu, C., Doi, H., Nukina, N.
  • Journal Title: EMBO J. 27 Pages: 827-839
  • Peer Reviewed
• [Journal Article] RNA-binding protein TLS is a major nuclear aggregate-interacting protein in huntingtin exon 1 with expanded polyglutamine-expressing cells. (2008)
  • Author(s): Doi, H., Okamura, K., Bauer, P.O., Furukawa, Y., Shimizu, H., Kurosawa, M., Machida, Y., Miyazaki, H., Mitsui, K., Kuroiwa, Y., Nukina, N.
  • Journal Title: J. Biol. Chem. 283 Pages: 6489-6500
  • Peer Reviewed
• [Journal Article] Blocking acid-sensing ion channel l alleviates Huntington's disease pathology via ubiquitin-proteasome system-dependent mechanism. (2008)
  • Author(s): Wong, H. K., et al.
  • Journal Title: Hum. Mol. Genet. 17 Pages: 3223-3235
  • Peer Reviewed
• [Journal Article] Mutant Huntingtin reduces HSP70 expression through the sequestration of NF-Y transcription factor. (2008)
  • Author(s): Yamanaka, T., et al.
  • Journal Title: EMBO J. 27 Pages: 827-839
  • Peer Reviewed
• [Journal Article] RNA-binding protein TLS is a major nuclear aggregate-interacting protein in huntingtin exon l with expanded polyglutamine-expressing cells. (2008)
  • Author(s): Doi, H., et al.
  • Journal Title: J. Biol. Chem. 283 Pages: 6489-6500
  • Peer Reviewed
• [Journal Article] Sodium channel beta4 subunit: down-regulation and possible involvement in neuritic degeneration in Huntington's disease transgenic mice. (2006)
  • Author(s): Oyama, F., Miyazaki, H., Sakamoto, N., Becquet, C., Machida, Y., Kaneko, K., Uchikawa, C., Suzuki, T., Kurosawa, M., Ikeda, T., Tamaoka, A., Sakurai, T., Nukina, N.
  • Journal Title: J. Neurochem. 98 Pages: 518-529
  • Peer Reviewed
• [Journal Article] Expression of expanded polyglutamine proteins suppresses the activation of transcription factor NF-kB. (2006)
  • Author(s): Goswami, A. et al.
  • Journal Title: J Biol Chem 281 Pages: 37017-37024
• [Journal Article] Expanded polyglutamines impair synaptic transmission and ubiquitin-proteasome system in Caenorhabditis elegans. (2006)
  • Author(s): Khan, L.A.et al.
  • Journal Title: J Neurochem 98 Pages: 576-587
• [Journal Article] Sodium channel beta4 subunit : down-regulation and possible involvement in neuritic degeneration in Huntington's disease transgenic mice. (2006)
  • Author(s): Oyama, F. et al.
  • Journal Title: J Neurochem 98 Pages: 518-529
• [Journal Article] rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse. (2006)
  • Author(s): Machida, Y. et al.
  • Journal Title: Biochem Biophys Res Commun 343 Pages: 190-197
• [Journal Article] Curcumin enhances the polyglutamine-expanded truncated N-terminal huntingtin-induced cell death by promoting proteasomal malfunction. (2006)
  • Author(s): Dikshit, P. et al.
  • Journal Title: Biochem Biophys Res Commun 342 Pages: 1323-1328
• [Journal Article] Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. (2006)
  • Author(s): Urushitani, M. et al.
  • Journal Title: Nat Neurosci 9 Pages: 108-118
• [Journal Article] Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. (2005)
  • Author(s): Iwata, A. et al.
  • Journal Title: Proc Natl Acad Sci U S A 102 Pages: 13135-13140
• [Journal Article] Dynamic expression of Hsp27 in the presence of mutant ataxin-3. (2005)
  • Author(s): Chang, W.H.et al.
  • Journal Title: Biochem Biophys Res Commun 336 Pages: 258-267
• [Journal Article] Decreased expression of hypothalamic neuropeptides in Huntington disease transgenic mice with expanded polyglutamine-EGFP fluorescent aggregates. (2005)
  • Author(s): Kotliarova, S. et al.
  • Journal Title: J Neurochem 93 Pages: 641-653
• [Journal Article] beta Subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase. (2005)
  • Author(s): Wong, H.K.et al.
  • Journal Title: J Biol Chem 280 Pages: 23009-23017
• [Journal Article] Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes. (2005)
  • Author(s): Jana, N.R.et al.
  • Journal Title: J Biol Chem 280 Pages: 11635-11640
• [Journal Article] Novel gene therapy for polyglutamine diseases to degrade selectively the pathogenic protein
  • Author(s): Bauer, P.O.et al.
  • Journal Title: Nat.Biotech. (in press)
  • Peer Reviewed
• [Journal Article] Mutant Huntingtin reduces HSP70 expression through the sequestration of NF-Y transcription factor.
  • Author(s): Yamanaka, T., et. al.
  • Journal Title: Embo J (in press)
  • Peer Reviewed
• [Journal Article] Genetic impairment of autophagy intensifies expanded polyglutamine toxicity in Caenorhabditis elegans. Biochem Biophys Res Commun (2008).
  • Author(s): Khan, L. A., et. al.
  • Journal Title: Biochem Biophys Res Commmun (in press)
  • Peer Reviewed
• [Journal Article] RNA-binding protein TLS is a major nuclear aggregate-interacting protein in Huntingtin exon 1 with expanded polyglutamine-exppressing cells.
  • Author(s): Doi, H., et. al.
  • Journal Title: J Biol Chem (in press)
  • Peer Reviewed
• [Presentation] New strategy for the treatment of polyglutamine diseases (2009)
  • Author(s): Nukina, N.
  • Organizer: International Conference "Protein folding and neurodegenerative disease"
  • Place of Presentation: Kyoto, Japan
• [Presentation] Amelioration of the pathological processes related to Huntington disease by targeting the mutant huntingtin to chaperone-mediated autophagy. (2008)
  • Author(s): Nukina, N., Bauer, P.O., Wong, H.K., Goswami, A., Miyazaki, H., Kurosawa, M., Yamada, M., Matsumoto, G.
  • Organizer: 38th Annual Meeting of Society for Neuroscience (Neuroscience 2008)
  • Place of Presentation: Washington, USA
• [Presentation] Amelioration of the pathological processes related to Huntington disease by targeting the mutant huntingtin to chaperone-mediated autophagy. (2008)
  • Author(s): Nukina, N., et al.
  • Organizer: 38^<th> Annual Meeting of Society for Neuroscience (Neuroscience2008)
  • Place of Presentation: Washington, USA
• [Presentation] Amiloride and its derivative ameliorate Huntington's disease pathological processes via an ubiquitin proteasome system-dependent mechanism. (2007)
  • Author(s): Wong, H. K., et. al.
  • Organizer: 37th Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego, USA
• [Presentation] Identification of aggregate interacting proteins in the polyglutamine diseases. (2006)
  • Author(s): Nukina, N., Doi, H., Yamanaka, T., Kino, Y., Furukawa, Y.
  • Organizer: 36th Annual Meeting of Society for Neuroscience (Neuroscience 2006)
  • Place of Presentation: Atlanta, USA
• [Remarks]
  • URL: http://www.brain.riken.jp/jp/n_nukina.html
• [Remarks]
  • URL: http://www.togo-nou.nips.ac.jp/
• [Remarks]
  • URL: http://www.togo-nou.nips.ac.jp/