Therapeutic strategy for polyglutamine-mediated motor neuron disease via molecular chaperone-ubiquitin proteasome system

• Project/Area Number: 20390243
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: ADACHI Hiroaki Nagoya University, 医学系研究科, COE特任講師 (40432257)
• Co-Investigator(Kenkyū-buntansha): SOBUE Gen 名古屋大学, 大学院・医学系研究科, 教授 (20148315) ; TANAKA Fumiaki 名古屋大学, 大学院・医学系研究科, 准教授 (30378012) ; KATSUNO Masahisa 名古屋大学, 高等研究院, 特任講師 (50402566)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2010: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2009: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2008: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: 球脊髄性筋萎縮症 / ポリグルタミン病 / 分子シャペロン / ペオニ抽出物 / アンドロゲン受容体 / CAGリピート / ユビキチン-プロテアソーム系 / 17-DMAG / Hsp90阻害剤 / トランスジェニックマウス / ユビキチンープロテアソーム系

Research Abstract

We administrated the peony extract to male spinal and bulbar muscular atrophy (SBMA) transgenic mouse model (androgen receptor (AR)-97Q or AR-24Q) and examined various neurological and behavioral parameters. Administration of the peony extract markedly ameliorated motor impairments in AR-97Q mice without detectable toxicity, and reduced amounts of monomeric and nuclear accumulated mutant AR. Mutant AR was preferentially degraded in the presence of the compound in both SBMA cell and mouse models when compared with wild-type AR. It also significantly induced Hsp70 and Hsp40. These observations suggest that the compound is a promising therapeutic candidate for polyglutamine (polyQ)-mediated neurodegenerative diseases including SBMA.

Research Products

• [Journal Article] Suppression of Alzheimer's disease-related phenotypes by expression of heat shock protein 70 in mice. (2011)
  • Author(s): Hoshino T, Murao N, Namba T, Takehara M, Adachi H, Katsuno M, Sobue G, Matsushima T, Suzuki T, Mizushima T.
  • Journal Title: J Neurosci31 Pages: 5225-5234
• [Journal Article] Transforming Growth Factor-β Signaling in Motor Neuron Diseases. (2011)
  • Author(s): Katsuno M, Adachi H, Banno H, Suzuki K, Tanaka F, Sobue G.
  • Journal Title: Curr Mol Med 11 Pages: 48-56
• [Journal Article] Suppression of Alzheimer's disease-related phenotypes by expression of heat shock protein 70 in mice (2011)
  • Author(s): Hoshino T, et al
  • Journal Title: J Neurosci Volume: (In press,In press)
  • Peer Reviewed
• [Journal Article] Microarray Analysis of Gene Expression by Skeletal Muscle of Three Mouse Models of Kennedy Disease/Spinal Bulbar Muscular Atrophy. (2010)
  • Author(s): Mo K, Razak Z, Rao Y, Yu Z, Adachi H, Katsuno M, Sobue G, Lieberman AP, Westwood JT, Monks DA.
  • Journal Title: PLoS ONE 5 Pages: 12922-12922
• [Journal Article] Clinicopathological features of acute autonomic and sensory neuropathy. (2010)
  • Author(s): Koike H, Atsuta N, Adachi H, Iijima M, Katsuno M, Yasuda T, Fukada Y, Yasui K, Nakashima K, Horiuchi M, Shiomi K, Fukui K, Takashima S, Morita Y, Kuniyoshi K, Hasegawa Y, Toribe Y, Kajiura M, Takeshita S, Mukai E, Sobue G.
  • Journal Title: Brain 133(10) Pages: 2881-2896
  • NAID: 10025625514
• [Journal Article] Clinical features and molecular mechanisms of spinal and bulbar muscular atrophy (SBMA). (2010)
  • Author(s): Katsuno M, Banno H, Suzuki K, Adachi H, Tanaka F, Sobue G.
  • Journal Title: Adv Exp Med Biol 685 Pages: 64-74
• [Journal Article] Disrupted transforming growth factor-beta signaling in spinal and bulbar muscular atrophy. (2010)
  • Author(s): Katsuno M, Adachi H, Minamiyama M, Waza M, Doi H, Kondo N, Mizoguchi H, Nitta A, Yamada K, Banno H, Suzuki K, Tanaka F, Sobue G.
  • Journal Title: J Neurosci 30 Pages: 5702-5712
• [Journal Article] Suppression of melanin production by expression of HSP70. (2010)
  • Author(s): Hoshino T, Matsuda M, Yamashita Y, Takehara M, Fukuya M, Mineda K, Maji D, Ihn H, Adachi H, Sobue G, Funasaka Y, Mizushima T.
  • Journal Title: J Biol Chem 285 Pages: 13254-13263
• [Journal Article] Prevention of ultraviolet B radiation-induced epidermal damage by expression of heat shock protein 70. (2010)
  • Author(s): Matsuda M, Hoshino T, Yamashita Y, Tanaka KI, Maji D, Sato K, Adachi H, Sobue G, Ihn H, Funasaka Y, Mizushima T.
  • Journal Title: J Biol Chem 285 Pages: 5848-5858
• [Journal Article] Dorfin ameliorates phenotypes in a transgenic mouse model of amyotrophic lateral sclerosis. (2010)
  • Author(s): Sone J, Niwa J, Kawai K, Ishigaki S, Yamada S, Adachi H, Katsuno M, Tanaka F, Doyu M, Sobue G.
  • Journal Title: J Neurosci Res 88 Pages: 123-135
• [Journal Article] Microarray Analysis of Gene Expression by Skeletal Muscle of Three Mouse Models of Kennedy Disease/Spinal Bulbar Muscular Atrophy (2010)
  • Author(s): Mo, et al
  • Journal Title: PLoS ONE Volume: 23
  • Peer Reviewed
• [Journal Article] Prevention of ultraviolet B radiation-induced epidermal damage by expression of heat shock protein 70 (2010)
  • Author(s): Matsuda M, et al
  • Journal Title: J Biol Chem Volume: 285 Pages: 5848-5858
  • Peer Reviewed
• [Journal Article] Heat shock proteins in neurodegenerative diseases : pathogenic roles and therapeutic implications. (2009)
  • Author(s): Adachi H, Katsuno M, Waza M, Minamiyama M, Tanaka F, Sobue G.
  • Journal Title: Int J Hyperthermia 25 Pages: 647-654
• [Journal Article] 17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in a SBMA model mouse. (2009)
  • Author(s): Tokui K*, Adachi H*, Waza M, Katsuno M, Minamiyama M, Doi H, Tanaka K, Hamazaki J, Murata S, Tanaka F, Sobue G.
  • Journal Title: Hum Mol Genet(* Evenly contributed to the study) 18 Pages: 898-910
• [Journal Article] Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. (2009)
  • Author(s): Banno H, Katsuno M, Suzuki K, Takeuchi Y, Kawashima M, Suga N, Takamori M, Ito M, Nakamura T, Matsuo K, Yamada S, Oki Y, Adachi H, Minamiyama M, Waza M, Atsuta N, Watanabe H, Fujimoto Y, Nakashima T, Tanaka F, Doyu M, Sobue G.
  • Journal Title: Ann Neurol 65 Pages: 140-150
• [Journal Article] Getting a handle on Huntington's disease : the case for cholesterol. (2009)
  • Author(s): Katsuno M, Adachi H, Sobue G.
  • Journal Title: Nat Med 15 Pages: 253-254
• [Journal Article] A role for HSP70 in protecting against indomethacin-induced gastric lesions. (2009)
  • Author(s): Suemasu S, Tanaka KI, Namba T, Ishihara T, Katsu T, Fujimoto M, Adachi H, Sobue G, Takeuchi K, Nakai A, Mizushima T.
  • Journal Title: J Biol Chem 284 Pages: 19705-19715
• [Journal Article] HSP70 Confers Protection against Indomethacin-Induced Lesions of the Small Intestine. (2009)
  • Author(s): Teita A, Tanaka KI, Yamakawa N, Adachi H, Sobue G, Goto H, Takeuchi K, Mizushima T.
  • Journal Title: J Pharmacol Exp Ther 330 Pages: 458-467
• [Journal Article] TDP-43 depletion induces neuronal cell damage through dysregulation of Rho family GTPases. (2009)
  • Author(s): Iguchi Y, Katsuno M, Niwa JI, Yamada SI, Sone J, Waza M, Adachi H, Tanaka F, Nagata KI, Arimura N, Watanabe T, Kaibuchi K, Sobue G.
  • Journal Title: J Biol Chem 284 Pages: 22059-22066
• [Journal Article] Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy. (2009)
  • Author(s): Palazzolo I, Stack C, Kong L, Musaro A, Adachi H, Katsuno M, Sobue G, Taylor JP, Sumner CJ, Fischbeck KH, Pennuto M.
  • Journal Title: Neuron 63 Pages: 316-328
• [Journal Article] 17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in a SBMA model mouse (2009)
  • Author(s): Tokui K, et al
  • Journal Title: Hum Mol Genet 18 Pages: 898-910
  • Peer Reviewed
• [Journal Article] Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy (2009)
  • Author(s): Banno H, et al
  • Journal Title: Ann Neurol 65 Pages: 140-150
  • Peer Reviewed
• [Journal Article] Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy (2009)
  • Author(s): Palazzolo I, et al
  • Journal Title: Neuron 63 Pages: 316-328
  • Peer Reviewed
• [Journal Article] 17-DMAG ameliorates polyglutamine-mediated motor neuron dege neration through well-preserved proteasorae function in a SBMA model mouse. (2009)
  • Author(s): Tokui K, et al
  • Journal Title: Hum Mol Genet 18 Pages: 898-910
  • Peer Reviewed
• [Journal Article] Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. (2009)
  • Author(s): Banno H, et al
  • Journal Title: Ann Neurol 65 Pages: 140-150
  • Peer Reviewed
• [Journal Article] Molecular genetics and biomarkers of polyglutamine diseases. (2008)
  • Author(s): Katsuno M, et al
  • Journal Title: Curr Mol Med 8 Pages: 221-234
  • Peer Reviewed
• [Presentation] A peony extract alleviates polyglutamine-mediated motor neuron disease (2010)
  • Author(s): Adachi H, Tohnai G, Katsuno M, Minamiyama M, Doi H, Matsumoto S, Kondo N, Miyazaki Y, Tanaka F, Ohtsuka K, Sobue G.
  • Organizer: 40th Annual Meeting for the Society for Neuroscience
  • Place of Presentation: San Diego
  • Year and Date: 2010-11-17
• [Presentation] A peony extract alleviates polyglutamine-mediated motor neuron disease (2010)
  • Author(s): Adachi H, et al
  • Organizer: Society for Neuroscience
  • Place of Presentation: San Diego conventioncenter (San Diego)
  • Year and Date: 2010-11-17
• [Presentation] TDP-43 depletion induces neuronal cell damage through dysregulation of Rho family GTPases (2009)
  • Author(s): Iguchi Y, Katsuno M, Niwa JI, Sone J, Waza M, Adachi H, Tanaka F, Nagata KI, Arimura N, Watanabe T, Kaibuchi K, Sobue G.
  • Organizer: 39th Annual Meeting for the Society for Neuroscience
  • Place of Presentation: Chicago, IL(一般演題)
  • Year and Date: 2009-10-18
• [Presentation] Medical induction of stress response alleviates polyglutamine-mediated motor neuron disease (2009)
  • Author(s): Tohnai G, et al
  • Organizer: The 4th International Congress Responses in Biology and Medicine (CSSI)
  • Place of Presentation: Sapporo
  • Year and Date: 2009-10-08
• [Presentation] Medical induction of stress response alleviates polyglutamine-mediated motor neuron disease The 4th International Congress Responses in Biology and Medicine (CSSI) (2009)
  • Author(s): Tohnai G, Adachi H, Tokui K, Waza M, Katsuno M, Minamiyama M, Doi H, Tanaka F, Ohtsuka K, Sobue G.
  • Organizer: The 4th Annual Meeting of The Biomedical Society for Stress Response (BSSR)
  • Place of Presentation: Sapporo(一般演題)
• [Presentation] SBMAモデルにおけるプロテアソーム機能と17-DMAGの治療効果 (2008)
  • Author(s): 足立弘明, ら
  • Organizer: 第3回臨床ストレス応答学会
  • Place of Presentation: 秋田
  • Year and Date: 2008-11-14
• [Presentation] An oral Hsp9O inhibitor ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model (2008)
  • Author(s): Adachi H, Tokui K, Katsuno M, Minamiyama M, Doi H, Tanaka F, Sobue G.
  • Organizer: 第38回The Society for Neuroscience Annual meeting
  • Place of Presentation: Washington DC(一般演題)