ポリグルタミン病の病態抑止療法の開発

2007 Fiscal Year Annual Research Report

• Project/Area Number: 19209033
• Research Institution: Nagoya University
• Principal Investigator: 祖父江 元 Nagoya University, 大学院・医学系研究科, 教授 (20148315)
• Co-Investigator(Kenkyū-buntansha): 田中 章景 名古屋大学, 大学院・医学系研究科, 准教授 (30378012) ; 足立 弘明 名古屋大学, 大学院・医学系研究科, COE特任講師 (40432257) ; 勝野 雅央 名古屋大学, 高等研究院, 特任講師 (50402566) ; 道勇 学 愛知医科大学, 医学部, 特任教授 (90293703)
• Keywords: ポリグルタミン / 分子シャペロン / ユビキチン・プロテアソーム / 熱ショック蛋白質

Research Abstract

球脊髄性筋萎縮症(SBMA)はアンドロゲン受容体のポリグルタミン鎖延長を原因とするポリグルタミン病である。我々は、これまで我々は、分子シャペロンの高発現や、薬剤による分子シャペロンの機能調節により、SBMAモデルマウスの病態が抑止されることを明らかにしてきた。今年度は、異常蛋白質の分解にあたって分子シャペロンとユビキチン・プロテアソーム系を連携する役割を果たすと考えられているCHIP (C terminus of Hsc70 (heat shock cognate protein 70)-interacting protein)に注目し、SBMAモデルマウスにおける神経変性の抑止効果を解析した。培養細胞にCHIPを過剰発現させると、異常伸長ポリグルタミン鎖を有する変異アンドロゲン受容体(AR)は野生型ARよりも効率的に分解を受けることが明らかとなった。CHIP高発現マウスとSBMAトランスジェニックマウスを交配し、ダブルトランスジェニックマウスを作成したところ、脊髄および骨格筋において変異ARの凝集体およびモノマーの分解が亢進し、抗ポリグルタミン免疫組織化学における核のびまん性染色が抑制された。マウスの神経症状および寿命はCHIPの高発現により著しく改善し、その効果はCHIPをヘテロで高発現した場合よりもホモで発現させたマウスにおいてより強く認められた。以上より、CHIPはポリグルタミン鎖の伸長した変異ARを効率的に分解することが示された。マウスにおいてCHIPを高発現させると熱ショック蛋白質の発現量や変異ARのmRNAレベルを変えることなく、変異ARの凝集体およびモノマーの量を減少させ、マウスにおける神経変性を抑止し、運動機能の増悪や寿命短縮といった表現型をCHIPの発現量依存的に著しく改善することが示された。CHIPは運動ニューロン疾患の治療ターゲットとして極めて重要であると考えられる。(799字)

Research Products

• [Journal Article] CAG repeat size correlates to electrophysiological motor and sensory phenotypes in SBMA (2008)
  • Author(s): Suzuki K, Katsuno M, Banno H, Yamashita F, Hori N, Nakamura T, Hirayama M, Tanaka F, Sobue G
  • Journal Title: Brain 131 Pages: 229-239
  • Peer Reviewed
• [Journal Article] ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor (2007)
  • Author(s): Yang, Z., Chang, Y. J., Yu, I. C., Yeh, S., Wu, C.C., Miyamoto, H., Merry, D. E., Sobue, G., Chen, L. M., Chang, S.S. & Chang, C
  • Journal Title: Nat. Med 13 Pages: 348-353
  • Peer Reviewed
• [Journal Article] Altered venous capacitanec as a cause of postprandial hypotension in multiple system atrophy (2007)
  • Author(s): Takamori M, Hirayama M, Kobayashi R, Ito H, Mabuchi N, Nakamura T, Hori N, Koike Y, Sobue G
  • Journal Title: Clin Auton Res 17 Pages: 20-25
  • Peer Reviewed
• [Journal Article] Reduces Mutant Androgen Receptor Protein and Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model (2007)
  • Author(s): Adachi H, Waza M, Tokui K, Katsuno M, Minamiyama M, Tanak F, Doyu M, Sobue G
  • Journal Title: J Neurosci 27 Pages: 5115-5126
  • Peer Reviewed
• [Journal Article] Congenial fibrosis of the extraocular muscles (CFEOM) sydrome associated with progressive cerebellar ataxia (2007)
  • Author(s): Yoshida K, Okano T, Hoshi K, Yahikozawa H, Suzuki K, Bannno H, Tamura T, Sobue G, Ikeda S
  • Journal Title: AM J Med Genet 143A Pages: 1494-1501
  • Peer Reviewed
• [Journal Article] Enhanced aquaporin-4 immunoreactivity in sporadic creutzfeldt-Jakob disease (2007)
  • Author(s): Iwasaki Y, Mimuro M, Yoshida M. Hashizume Y, Ito M, Kitamoto T, Wakayama Y, Sobue G
  • Journal Title: Neuropathology 27 Pages: 314-323
  • Peer Reviewed
• [Journal Article] Widespread Spinal cord invovement in progressive in supranuclear plasy (2007)
  • Author(s): Iwasaki Y, Yoshida M. Hashizume Y, Hattori M, Aiba I, Sobue G
  • Journal Title: Neuropathology 27 Pages: 331-340
  • Peer Reviewed
• [Journal Article] Gene expressions specifically detected in motor neurons (dynactin l, early growth response 3, Acetyl-CoA transporter, death receptor 5, and cyclin C) differentially correlate to athologic markers in sporadic amyotrophic lateral sclerosis (2007)
  • Author(s): Jiang Y, Yamamoto M, Tanaka F, Ishigaki S, Katsuno M, Adachi H, Niwia J, Doyu M, Yoshida M, Hashizume Y, Sobue G
  • Journal Title: Neuropathol Exp Neurol 66 Pages: 617-627
  • Peer Reviewed
• [Journal Article] Ataxic vs painful form of paraneoplastic neuropathy (2007)
  • Author(s): Oki Y, Koike H, Iijima M, Mori K, Hattori N, Katsuno M, Nakamura T, Hirayama M, Tanaka F, Shiraishi M, Yazaki S, Nokura K, Yamamoto H,Sobue G
  • Journal Title: Neurology 69 Pages: 564-572
  • Peer Reviewed
• [Journal Article] Genetic evidence for a protective role for heat shock factor l and heat shock protein 70 against colitis (2007)
  • Author(s): Tanaka K, Namba T, Arai Y, Fujimoto M, Adachi H, Sobue G, Takeuchi K, Nakai A, Mizushima T
  • Journal Title: J Biol Chem 282 Pages: 23240-23252
  • Peer Reviewed
• [Journal Article] Disulfide bond mediates aggregation, toxicity, and ubiquitylation of familial amyotrophic lateral sclerosis-linked mutant SOD1 (2007)
  • Author(s): Niwa J, Yamada S, Ishigaki S, Sone J, Takahashi M, Katsuno M, Tanaka F, Doyu M, Sobue G
  • Journal Title: J Biol Chem 282 Pages: 28087-28095
  • Peer Reviewed
• [Journal Article] Recent progress in alcoholic and thiamine-deficiency neuropathy (2007)
  • Author(s): Koike H, Oki Y, Iijima M, katsuno M, Hattori N, Sobue G
  • Journal Title: Current trend in Neurology 2 Pages: 79-85
  • Peer Reviewed
• [Journal Article] Therapeutic strategies for spinal and bulbar musculara atrophy (SBMA) (2007)
  • Author(s): Katsuno M, Bannno H, Suzuki K, Takeuchi Y, Minamiyama M, Waza M, Adachi H, Tanaka F, Sobue G
  • Journal Title: Drugns of the Future 32 Pages: 907-917
  • Peer Reviewed
• [Journal Article] Nonmyelinating Schwann cell involvement with well-preserved unmyelinated axons in Charco-Matie-Tooth disease type 1A (2007)
  • Author(s): Koike H, Iijima M, Mori K, Yamamoto M, Hattori N, Katsuno M, Tanaka F, Watanabe H, Doyu M, Yoshikawa H, Sobue G
  • Journal Title: J Neuropathol Exp Neurol 66 Pages: 1027-1036
  • Peer Reviewed
• [Journal Article] Dobutamine stress test unmasks cardiac sympathetic denervation in Parkinson's disease (2007)
  • Author(s): Nakamura T, Hirayama M, Ito H, Takamori M, Hamada K, Takeuchi S, Watanabe H, Koike Y, Sobue G
  • Journal Title: J Neurol Sci 263 Pages: 133-138
  • Peer Reviewed
• [Journal Article] Pyramidal tract degeneration in sporadic Creutzfeldt-Jakob disease (2007)
  • Author(s): Iwasaki Y, Yoshida M, Hashizume Y, Kitamoto T, Sobue G
  • Journal Title: Neuropathology 27 Pages: 434-441
  • Peer Reviewed
• [Journal Article] Hypophosphataemic neuropathy in a patient who received intravenous hyperalimentation (2007)
  • Author(s): Iguchi Y, Mori K, Koike H, Mano K, Goto Y, Kato T, Nakano T, Furukawa D, Sobue G
  • Journal Title: Neurol Neurosurg Psychiatry 78 Pages: 1159-1160
  • Peer Reviewed
• [Journal Article] In vitro and in silico analysis reveals an efficient algorithm to predict the splicing consequences of mutations at the 5'splice sites (2007)
  • Author(s): Sahashi K, Masuda A, Matsuura T, Shinmi J, Zhang Z, Takeshima Y, Matsuo M, Sobue G, Ohno K
  • Journal Title: Nucleic Acids Res 35 Pages: 5995-6003
  • Peer Reviewed
• [Journal Article] Intravenous immunoglobulin therapy markedly ameliorates muscle weakness and severe pain in proximal diabetic neuropathy (2007)
  • Author(s): Kawagashira Y, Watanabe H, Oki Y, Iijima M, Koike H, Hattori N, Katsuno M, Tanaka F, Sobue G
  • Journal Title: J Neurol Neurosurg Psychiatry 78 Pages: 899-901
  • Peer Reviewed
• [Journal Article] Scientific highlights. 17th International Symposium on ALS/MND Yokohama, Japan, November 30, 2006 through December 2, 2006 (2007)
  • Author(s): Sobue G
  • Journal Title: Amyotroph Lateral Scler (2) Pages: 121-123
  • Peer Reviewed
• [Journal Article] Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy (2007)
  • Author(s): Adachi H, Waza M, Katsuno M, Tanaka F, Doyu M, Sobue G
  • Journal Title: Neuropathol Appl Neurobiol 33 Pages: 135-151
  • Peer Reviewed
• [Journal Article] Usefulness of combined fractional anisotropy and apparent diffusion coefficient values for detection of involvement in multiple system atropyh (2007)
  • Author(s): Ito M, Watanabe H, Kawai Y, Atsuta N, Tanaka F, Naganawa S, Fukatsu H, Sobue G
  • Journal Title: J Neurol Neurosurg Psychiatry 78 Pages: 722-728
  • Peer Reviewed
• [Journal Article] ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor (2007)
  • Author(s): Yang Z, Chang YJ, Yu IC, Yeh S, Wu CC, Miyamoto H, Merry DE, Sobue G, Chen LM, Chang SS, Chang C
  • Journal Title: Nat Med 13 Pages: 348-353
  • Peer Reviewed
• [Journal Article] Dorfin-CHIP chimeric proteins potently ubiquitylate and degrade familial ALS-related mutant SODI proteins and reduce their cellular toxicity (2007)
  • Author(s): Ishigaki S, Niwa J, Yamada S, Takahashi M, Ito T, Sone J, Doyu M, Urano F, Sobue G
  • Journal Title: Neurobiol Dis 25 Pages: 331-241
  • Peer Reviewed