Analysis of synapse pathology underlying the spinocerebellar ataxia

脊髓小脑共济失调的突触病理学分析

• 批准号: 24800008
• 负责人: SHUVAEV Anton
• 金额: $ 1.91万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Research Activity Start-up
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-08-31 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-24800008/
• 关键词: 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

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.

表现出严重的小脑共济失调的错位突变小鼠是由核转录因子，类维质相关的孤儿受体α（Roralpha）的功能丧失引起的，并且在Purkinje细胞中表现出完全丧失的代孕型谷氨酸受体亚型亚型亚型1（MGLUR1） - 介导的信号传导。已经表明，脊椎队共济失调1型（SCA1小鼠）的模型小鼠在Purkinje细胞中表现出明显较低的Roralpha水平，因此，我们假设在SCA1小鼠中也会损害mglur信号传导。我们的电生理实验表明，SCA1小鼠中MGLUR信号传导的明显缺陷。此外，一种增强MGLUR信号传导的药理治疗可改善SCA1小鼠的小脑运动学习。这些结果表明通过MGLUR1对SCA1患者进行了潜在的治疗干预。

项目成果

Impalrment of metabotropic glutamate receptor signaling in mouse Purkinje cells expressing a mutant gene of spinocerebellar ataxia type1

表达脊髓小脑共济失调 1 型突变基因的小鼠浦肯野细胞代谢型谷氨酸受体信号传导受损

• 发表时间: 2012
• 作者: Shuvaev AN;Yamato S;Hanna Goenovan;Yanagihara D;Hirai H
• 通讯作者: Hirai H

Disruption of metabotropic glutamate receptor signaling in Purkinje cells expressing a lentivirally transduced mutant SCA1

表达慢病毒转导突变体 SCA1 的浦肯野细胞中代谢型谷氨酸受体信号传导的破坏

• 发表时间: 2013
• 作者: Konno A;Shuvaev AN;Yanagi S;and Hirai H;Shuvaev AN
• 通讯作者: Shuvaev AN

Disruption of metabotropic glutamate receptor signaling in Purkinje cells expressing a lentivirally transduced mutant SCA1 gene

表达慢病毒转导的突变型 SCA1 基因的浦肯野细胞中代谢型谷氨酸受体信号传导的破坏

• 发表时间: 2013
• 作者: Shuvaev AN;Sato Y;Goenawan H,Yanagihara D;and Hirai H
• 通讯作者: and Hirai H

Disruption of mGluR signaling in SCA3 model mice expressing mutant ataxin-3 and the partial restorationvia intravenous administration of AAV9

表达突变ataxin-3的SCA3模型小鼠中mGluR信号传导的破坏以及通过静脉注射AAV9的部分恢复

• 发表时间: 2013
• 作者: Konno A;Shuvaev AN;Yanagi S;and Hirai H
• 通讯作者: and Hirai H

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

脊髓小脑变性 3 型小鼠模型中 mGluR1 的功能障碍及其通过 AAV9 基因治疗的功能恢复

• 发表时间: 2013
• 作者: 今野 歩;Shuvaev Anton;三宅 紀子;三宅 弘一;柳 茂;島田 隆;平井 宏和
• 通讯作者: 平井 宏和