Identification of therapeutic targets for ALS by screening for TDP-43 and FUS associated molecules

通过筛选 TDP-43 和 FUS 相关分子鉴定 ALS 治疗靶点

• 批准号: 23659452
• 负责人: SOBUE Gen
• 金额: $ 2.33万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23659452/
• 关键词: 筋萎縮性側索硬化症; ALS; FUS; 小胞体ストレス; 改変GFP; 検知システム; 神経変性疾患モデル細胞

Mouse primary cortical neurons were silenced with FUS by introducing lentivirus encoding shRNA against FUS gene. We next established the FUS-regulated transcriptome profiles of primary neurons using exon-sensitive microarrays and identified that FUS regulated the alternative splicing of Mapt exon10. This alternative splicing event results in three-repeats (RD3) and four-repeats (RD4) Tau isoform production and the ratio of RD4/RD3 was increased when FUS was silenced in neurons. Morphological abnormality of neurite was observed in FUS-silenced primary neurons and it was rescued bysilencing of RD4. These findings suggest that RD4 could be a therapeutic target for ALS treatment.

通过引入编码针对FUS基因的shRNA的慢病毒，用FUS沉默小鼠原代皮层神经元。接下来，我们使用外显子敏感的微阵列建立了FUS调节的原代神经元转录组谱，并确定FUS调节Mapt外显子10的选择性剪接。这种选择性剪接事件导致三重复（RD 3）和四重复（RD 4）Tau同种型的产生，并且当神经元中FUS沉默时，RD 4/RD 3的比率增加。在FUS沉默的原代神经元中观察到突起的形态学异常，并通过沉默RD 4来挽救。这些发现表明RD 4可能是ALS治疗的治疗靶点。

项目成果

Loss of TDP-43 causes age-dependent progressive motor neuron degeneration

• DOI: 10.1093/brain/awt029
• 发表时间: 2013-05-01
• 期刊: BRAIN
• 影响因子: 14.5
• 作者: Iguchi, Yohei;Katsuno, Masahisa;Sobue, Gen
• 通讯作者: Sobue, Gen

Comparison of Fus-regulating gene expression and alternative splicing profiles among different cell lineages in the central nervous system

中枢神经系统不同细胞谱系中 Fus 调节基因表达和选择性剪接谱的比较

• 发表时间: 2012
• 作者: Shinsuke Ishigaki;Yusuke Fujioka;Akio Masuda;Yohei Iguchi;Masahisa Katsuno;Kinji Ohno;and Gen Sobue
• 通讯作者: and Gen Sobue

Quality loss of FUS function is involved in the pathogenesis of ALS.

FUS 功能的质量丧失与 ALS 的发病机制有关。

• 发表时间: 2011
• 作者: Shinsuke Ishigaki;Yusuke Fujioka;and Gen Sobue
• 通讯作者: and Gen Sobue

Profiles of differential gene expression and alternative splicing in FUS knock-down primary motor neurons.

FUS 敲低初级运动神经元中差异基因表达和选择性剪接的概况。

• 发表时间: 2011
• 作者: Yusuke Fujioka;Shinsuke Ishigaki;and Gen Sobue
• 通讯作者: and Gen Sobue

運動ニューロンにおけるALS関連変異FUS/TLSの機能障害

ALS 相关运动神经元突变 FUS/TLS 功能障碍

• 发表时间: 2011
• 作者: 石垣診祐;藤岡祐介;田中章景;祖父江元
• 通讯作者: 祖父江元