Study on the mechanism of aggregate formation in neurodegeneration

2009 Fiscal Year Final Research Report

• 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
• 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

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 Pages: e7275
  • 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] 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] 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
• [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
  • Year and Date: 20081115-20081119
• [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
  • Year and Date: 20061014-20061018
• [Remarks]
  • URL: http://www.brain.riken.jp/jp/n_nukina.html