Analysis of synapse pathology underlying the spinocerebellar ataxia

• Project/Area Number: 24800008
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Neurophysiology and muscle physiology
• Research Institution: Gunma University
• Principal Investigator: SHUVAEV Anton 群馬大学, 医学(系)研究科(研究院), 研究員 (30633771)
• Project Period (FY): 2012-08-31 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: spinocerebellar ataxia / cerebellum / Purkinje cell / glutamate receptor / patch clamp / 脊髄小脳変性症 / 小脳 / プルキンエ細胞 / グルタミン酸受容体 / 代謝型グルタミン酸受容体 / グルタミン酸トランスポーター / パッチクランプ

Research Abstract

Staggerer mutant mice, which show severe cerebellar ataxia, are caused by functional loss of a nuclear transcription factor, retinoid-related orphan receptor alpha (RORalpha) and exhibit complete loss of metabotropic glutamate receptor subtype 1 (mGluR1)-mediated signaling in Purkinje cells. It has been shown that model mice of spinocerebellar ataxia type 1 (SCA1 mice) express significantly lower levels of RORalpha in Purkinje cells and therefore, we hypothesized that mGluR signaling was impaired also in SCA1 mice. Our electrophysiology experiments revealed significant defects of mGluR signaling in SCA1 mice. Moreover, a pharmacological treatment that enhanced mGluR signaling improved cerebellar motor learning in SCA1 mice. These results suggest the potential therapeutic intervention for SCA1 patients through mGluR1.

Research Products

• [Journal Article] Mutant Ataxin-3 with an Abnormally Expanded Polyglutamine Chain Disrupts Dendritic Development and Metabotropic Glutamate Receptor Signaling in Mouse Cerebellar Purkinje Cells (2014)
  • Author(s): Konno A, Shuvaev AN, Miyake N, Miyake K, Iizuka A, Matsuura S, Huda F, Nakamura K, Yanagi S, Shimada T, and Hirai H
  • Journal Title: Cerebellum Volume: 13(1) Pages: 29-41
  • Peer Reviewed
• [Journal Article] Mutant ataxin-3 with an abnormally expanded polyglutamine chain disrupts dendritic development and metabotropic glutamate receptor signaling in mouse cerebellar purkinje cells (2014)
  • Author(s): Konno A, Shuvaev AN, Miyake N, Miyake K, Iizuka A, Matsuura S, Huda F, Nakamura K, Yanagi S, Shimada T, Hirai H.
  • Journal Title: Cerebellum Volume: 13 Issue: 1 Pages: 29-41
  • DOI: 10.1007/s12311-013-0516-5
  • Peer Reviewed
• [Journal Article] Mesenchymal Stem Cells Ameliorate Cerebellar Pathology in a Mouse Model of Spinocerebellar Ataxia Type 1 (2013)
  • Author(s): Matsuura S, Shuvaev AN, Iizuka A, Nakamura K, and Hirai H
  • Journal Title: Cerebellum Volume: (Epub ahead of print)
  • Peer Reviewed
• [Presentation] Perturbation of mGluR signaling in SCA3 model mice expressing mutant ataxin-3 and the rescue by intravascular administration of AAV9 (2013)
  • Author(s): Konno A, Shuvaev AN, Yanagi S, and Hirai H
  • Organizer: 23rd Neuropharmacology Conference
  • Place of Presentation: サンディエゴ
• [Presentation] Disruption of mGluR signaling in SCA3 model mice expressing mutant ataxin-3 and the partial restorationvia intravenous administration of AAV9 (2013)
  • Author(s): Konno A, Shuvaev AN, Yanagi S, and Hirai H
  • Organizer: Neuroscience 2013
  • Place of Presentation: サンディエゴ
• [Presentation] Disruption of metabotropic glutamate receptor signaling in Purkinje cells expressing a lentivirally transduced mutant SCA1 (2013)
  • Author(s): Shuvaev AN
  • Organizer: 第19回日本遺伝子治療学会学術集会
  • Place of Presentation: 岡山
• [Presentation] Disruption of metabotropic glutamate receptor signaling and rescue throughintravasucular administration of AAV9 in a mouse model of spinocerebellar ataxia type 3 (2013)
  • Author(s): Konno A, Shuvaev AN, Miyake N, Miyake K, Yanagi S, ShimadaT, and Hirai H
  • Organizer: 第19回日本遺伝子治療学会学術集会
  • Place of Presentation: 岡山
• [Presentation] Disruption of metabotropic glutamate receptor signaling in Purkinje cells expressing a lentivirally transduced mutant SCA1 gene (2013)
  • Author(s): Shuvaev AN, Sato Y, Goenawan H,Yanagihara D, and Hirai H
  • Organizer: Neuro2013
  • Place of Presentation: Kyoto
• [Presentation] 脊髄小脳変性症3型マウスモデルにおけるmGluR1の機能不全とAAV9を用いた遺伝子治療によるその機能回復 (2013)
  • Author(s): 今野歩, Shuvaev AN, 三宅紀子, 三宅弘一, 柳茂, 島田隆, 平井宏和
  • Organizer: Neuro2013
  • Place of Presentation: 京都
• [Presentation] Perturbation of mGluR signaling in SCA3 model mice expressing mutant ataxin-3 and the rescue by intravascular administration of AAV9 (2013)
  • Author(s): Konno A, Shuvaev A, Yanagi S, Hirai H.
  • Organizer: 23rd Neuropharmacology Conference
  • Place of Presentation: サンディエゴ
• [Presentation] Disruption of metabotropic glutamate receptor signaling in Purkinje cells expressing a lentivirally transduced mutant SCA1 gene (2013)
  • Author(s): Shuvaev AN, Sato Y, Goenawan H,Yanagihara D, Hirai H
  • Organizer: Neuro2013
  • Place of Presentation: 京都
• [Presentation] 脊髄小脳変性症３型マウスモデルにおけるmGluR1の機能不全とAAV9を用いた遺伝子治療によるその機能回復 (2013)
  • Author(s): 今野 歩、Shuvaev Anton、三宅 紀子、三宅 弘一、柳 茂、島田 隆、平井 宏和
  • Organizer: Neuro2013
  • Place of Presentation: 京都
• [Presentation] AAV9の静脈注射による脊髄小脳変性症3型モデルマウスへの遺伝子治療の試み (2012)
  • Author(s): 今野歩, Shuvaev AN, 三宅紀子, 三宅弘一, 柳茂, 島田隆, 平井宏和
  • Organizer: 第35回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] Impalrment of metabotropic glutamate receptor signaling in mouse Purkinje cells expressing a mutant gene of spinocerebellar ataxia type1 (2012)
  • Author(s): Shuvaev AN, Yamato S, Hanna Goenovan, Yanagihara D, and Hirai H
  • Organizer: 第35回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] Impalrment of metabotropic glutamate receptor signaling in mouse Purkinje cells expressing a mutant gene of spinocerebellar ataxia type1 (2012)
  • Author(s): Shuvaev AN, Yamato S, Hanna Goenovan, Yanagihara D, Hirai H
  • Organizer: 第３５回日本神経科学大会
  • Place of Presentation: 名古屋