ポリグルタミン病の病態解明とそれに基づく治療法の開発

2007 Fiscal Year Annual Research Report

• Project/Area Number: 17025020
• 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) ; 服部 直樹 名古屋大学, 医学部・附属病院, 助教 (10402570) ; 勝野 雅央 名古屋大学, 高等研究院, 特任講師 (50402566)
• Keywords: ポリグルタミン病 / 球脊髄性筋萎縮症 / ユビキチン / プロテアソーム / CHIP

Research Abstract

これまで我々は、分子シャペロンの機能調節によるポリグルタミン病の病態抑止を検討してきた。今年度は、分子シャペロンとユビキチン・プロテアソーム系をつなぐ役割を果たすと考えられているC terminus of Hsc70-interacting protein(CHIP)の球脊髄性筋萎縮症(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。培養細胞においてCHIPはポリグルタミン鎖の延長したアンドロゲン受容体(AR)のユビキチン化および分解を促進した。チキンβアクチンプロモーター下でCHIPおよびmycタグを発現するトランスジェニックマウスを作成し、野生型のARを発現するマウス(AR-24Q)またはSBMAモデルマウス(AR-97Q)と交配したところ、CHIPを高発現したAR-97Qマウス脊髄および骨格筋では変異ARの凝集体およびモノマーの減少が認められたが、こうした効果はAR-24Qマウスでは認められなかった。また、CHIP高発現による分子シャペロンの発現量の変化についても脊髄および骨格筋において解析したが、Hsp70、Hsp90、Hsp40の発現量に変化は認められなかった。CHIPを高発現したAR-97Qマウスではロータロッド、ケージアクティビティー、歩幅、体重、生存期間の有意な改善が認められ、とくにその効果はCHIPをホモで高発現するマウスにおいて強く認められた。病理学的には、脊髄前角および骨格筋のいずれにおいても抗ポリグルタミン抗体で核がびまん性に染色される細胞数が減少し、骨格筋のHE染色では神経原性筋萎縮の所見にも改善が認められた。脊髄前角のGFAP染色では反応性グリオーシスの減弱が示唆された。
以上より、CHIPは変異アンドロゲン受容体のプロテアソームによる分解を促進し、神経変性を抑止する作用を有していることが明らかとなった。(786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, Takeuchi Y, Atsuta N, Ito M, Watanabe 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 capacitance 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 supranuclear palsy (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 1, 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 1 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 atrophy (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