Elucidation of cellular signaling defect and mechanism of cell-specific degeneration in polyglutamine diseases

阐明多聚谷氨酰胺疾病中的细胞信号缺陷和细胞特异性变性机制

• 批准号: 21689024
• 负责人: KATSUNO Masahisa
• 金额: $ 17.8万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (A)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21689024/
• 关键词: ポリグルタミン病; 運動ニューロン; TGF-βシグナル; 球脊髄性筋萎縮症; ポリグルタミン; アンドロゲン受容体; HSF-1; HSP70; 分子シャペロン; 神経変性; NF-Y; TGF-beta; 転写障害; Smad2

Spinal and bulbar muscular atrophy (SBMA) is a late-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat in androgen receptor (AR). Although it is commonly held that the pathogenic polyglutamine proteins induce transcriptional dysregulation, the down-stream molecular events have remained elusive. Here we examined whether TGF-βsignaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2/3 is suppressed in the spinal motor neurons of male transgenic mice carrying the mutant human AR. The pathogenic AR inhibits the transcription of TGF-βreceptor type II (TβRII), via abnormal interactions with NF-Y and p300/CBP-associated factor (P/CAF). Furthermore, overexpression of TβRII dampens the cytotoxicity of the pathogenic AR. The present study thus indicates that disruption of TGF-βdue to the transcriptional dysregulation of TβRII is associated with polyglutamine-induced motor neuron damage in SBMA.

脊髓延髓肌萎缩症（SBMA）是一种迟发性下运动神经元疾病，由雄激素受体（AR）中的三核苷酸CAG重复序列扩增引起。虽然人们普遍认为致病性多聚谷氨酰胺蛋白诱导转录失调，下游分子事件仍然难以捉摸。在这里，我们研究了TGF-β信号转导是否在SBMA中失调。在携带突变型人AR的雄性转基因小鼠的脊髓运动神经元中，磷酸化Smad 2/3的核转位受到抑制。致病性AR通过与NF-Y和p300/CBP相关因子（P/CAF）的异常相互作用抑制TGF-β受体II（TβRII）的转录。此外，TβRII的过表达减弱了致病性AR的细胞毒性。因此，本研究表明，由于TβRII转录失调导致的TGF-β破坏与多聚谷氨酰胺诱导的SBMA运动神经元损伤有关。

项目成果

The profile of motor unit number estimation (MUNE) in spinal and bulbar muscular atrophy

• DOI: 10.1136/jnnp.2009.190462
• 发表时间: 2009-12
• 期刊: Journal of Neurology, Neurosurgery & Psychiatry
• 作者: Keisuke Suzuki;M. Katsuno;H. Banno;Y. Takeuchi;Motoshi Kawashima;Noriaki Suga;A. Hashizume;T. Hama;K. Uchida;Fumitada Yamashita;Tomohiko Nakamura;M. Hirayama;F. Tanaka;G. Sobue

Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial

• DOI: 10.1016/s1474-4422(10)70182-4
• 发表时间: 2010-09-01
• 期刊: LANCET NEUROLOGY
• 影响因子: 48
• 作者: Katsuno, Masahisa;Banno, Haruhiko;Sobue, Gen
• 通讯作者: Sobue, Gen

Transforming growth factor-beta signaling in motor neuron diseases.

• DOI: 10.2174/156652411794474356
• 发表时间: 2011-02-01
• 期刊: Current molecular medicine
• 影响因子: 2.5
• 作者: Katsuno, M;Adachi, H;Sobue, G
• 通讯作者: Sobue, G

icroarray analysis of gene expression by skeletal muscle of three mouse models of kennedy disease/spinal bulbar muscular atrophy.

对三种肯尼迪病/脊髓延髓肌萎缩症小鼠模型骨骼肌基因表达的微阵列分析。

• 发表时间: 2010
• 期刊: PLoS One 5
• 作者: Mo K;Razak Z;Rao P;Yu Z;Adachi H;Katsuno M;Sobue G;Lieberman AP;Westwood JT;Monks DA.M
• 通讯作者: Monks DA.M

for the Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) study group.Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study) : a multicentre, randomised, double-blind, placebo-controlled trial.

日本 SBMA TAP-144-SR 介入试验 (JASMITT) 研究组。亮丙瑞林对脊髓和延髓肌萎缩患者的疗效和安全性（JASMITT 研究）：一项多中心、随机、双盲、安慰剂对照试验。

• 发表时间: 2010
• 期刊: Lancet Neurol. 9
• 作者: Katsuno M;Banno H;Suzuki K;Takeuchi Y;Kawashima M;Yabe I;Sasaki H;Aoki M;Morita M;Nakano I;Kanai K;Ito S;Ishikawa K;Mizusawa H;Yamamoto T;Tsuji S;Hasegawa K;Shimohata T;Nishizawa M;Miyajima H;Kanda F;Watanabe Y;Nakashima K;Tsujino A
• 通讯作者: Tsujino A