Investigation of effect of TDP-43 aggregation on translational control

TDP-43 聚集对翻译控制的影响研究

• 批准号: 23791008
• 负责人: HIGASHI Shinji
• 金额: $ 2.41万
• 依托单位: 公益財団法人東京都医学総合研究所 (2012)Tokyo Metropolitan Organization for Medical Research (2011)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 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-23791008/
• 关键词: 神経科学; 神経変性疾患; 筋萎縮性側索硬化症; 前頭側頭型認知症; TDP-43; ストレス顆粒; 酸化ストレス; 細胞死; 筋委縮性側索硬化症; 前頭側頭葉変性症; 神経変性; RNA代謝

TDP-43 has emerged as an important contributor to amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Polysome profiling analysis revealed that oxidative stress caused the association of TDP-43 with stalled ribosomes via binding to mRNA. When the cells were exposed to short-term/non-lethal stress, TDP-43 associating with ribosomes localized to stress granules (SGs) and this association was transient. In contrast, when the cells were exposed to long-term/sublethal stress, TDP-43 was excluded from SGs and shifted to the heavy fractions independent of any binding to mRNA. In these severely stressed cells, TDP-43 was insolubilized and phosphorylated. In TDP-43-silenced cells, stalled mRNA and poly (A)+ RNA stability was disturbed and cytotoxicity increased under sublethal stress.

TDP-43已成为肌萎缩侧索硬化症和额颞叶变性的重要贡献者。多核糖体分析表明，氧化应激导致TDP-43通过与mRNA结合而与停滞的核糖体相关联。当细胞暴露于短期/非致死性应激时，TDP-43与核糖体的结合定位于应激颗粒（SG），并且这种结合是短暂的。相反，当细胞暴露于长期/亚致死应激时，TDP-43被排除在SG之外，并转移到与mRNA无关的重组分。在这些严重应激的细胞中，TDP-43不溶解并磷酸化。在TDP-43沉默的细胞中，停滞的mRNA和poly（A）+ RNA的稳定性被扰乱，并且在亚致死胁迫下细胞毒性增加。

项目成果

Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain

• DOI: 10.1007/s00401-012-0984-6
• 发表时间: 2012-09-01
• 期刊: ACTA NEUROPATHOLOGICA
• 影响因子: 12.7
• 作者: Aoki, Naoya;Higashi, Shinji;Akiyama, Haruhiko
• 通讯作者: Akiyama, Haruhiko

TDP-43 associates with stalled ribosomes and contributes to cell survival during cellular stress

• DOI: 10.1111/jnc.12194
• 发表时间: 2013-07-01
• 期刊: JOURNAL OF NEUROCHEMISTRY
• 影响因子: 4.7
• 作者: Higashi, Shinji;Kabuta, Tomohiro;Wada, Keiji
• 通讯作者: Wada, Keiji