Novel pathological pathway of ALS/FTLD-U

ALS/FTLD-U的新病理通路

• 批准号: 23591254
• 负责人: ITO Daisuke
• 金额: $ 3.49万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23591254/
• 关键词: ubiquitin; optineurin; 筋萎縮性側策硬化症; endosome; autophagy; 前頭側頭葉変性症; TDP-43; FUS; ubiquilin; RNA; Ataxin2

Ubiquilin (UBQLN) 2 localized in endosomal vesicles formed by the ALS-linked molecule optineurin (OPTN) and also co-localized with an initiator of the autophagic process, ULK1, after amino acid starvation. OPTN-vesicles were ubiquitin- and p62-immunopositive. An ALS-linked mutation (E478G) in OPTN abolished vesicle formation. ALS-linked mutations in UBQLN2 additively enhanced UBQLN2 aggregation and formation of inclusion bodies, resulting in mislocation from OPTN-vesicles. UBQLN2 was found to be a potent regulator of the levels of OPTN and the FTD-linked secretory factor progranulin, possibly via the endosomal system, and ALS-linked mutations disturbed these functional consequences. This study demonstrates that ALS-linked mutations in both OPTN and UBQLN2 interfere with the constitution of specific endosomal vesicles, suggesting that the vesicles are involved in protein homeostasis and that these proteins function in common pathological processes.

泛素（UBQLN）2定位于由ALS连接的分子视神经磷酸酶（OPTN）形成的内体囊泡中，并且在氨基酸饥饿后与自噬过程的起始物ULK 1共定位。OPTN囊泡呈泛蛋白和p62免疫阳性。OPTN中的ALS连锁突变（E478G）消除了囊泡形成。UBQLN 2中的ALS连锁突变增加了UBQLN 2的聚集和包涵体的形成，导致从OPTN囊泡的错误定位。发现UBQLN 2是OPTN和FTD相关分泌因子颗粒蛋白前体水平的有效调节剂，可能通过内体系统，ALS相关突变扰乱了这些功能结果。这项研究表明，ALS连锁突变的OPTN和UBQLN 2干扰特定的内体囊泡的构成，这表明囊泡参与蛋白质稳态，这些蛋白质在共同的病理过程中发挥作用。

项目成果

Establishment of induced pluripotent stem cells from centenarians for neurodegenerative disease research.

建立来自百岁老人神经退行性疾病研究的诱导多能干细胞。

• DOI: 10.1371/journal.pone.0041572
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Yagi T;Kosakai A;Ito D;Okada Y;Akamatsu W;Nihei Y;Nabetani A;Ishikawa F;Arai Y;Hirose N;Okano H;Suzuki N
• 通讯作者: Suzuki N

Generation of iPS cells from centenarians for neurodegenerative disease research.

从百岁老人身上生成 iPS 细胞，用于神经退行性疾病研究。

• 作者: 八木拓也;小堺有史;伊東大介;岡田洋平;赤松和土;二瓶義廣;鍋谷彰;石川冬木;広瀬信義;岡野栄之;鈴木則.
• 通讯作者: 鈴木則.

Meningoencephalopathy as a clinical manifestation of Epstein–Barr virus‐associated hemophagocytic syndrome

脑膜脑病是 Epstein-Barr 病毒相关噬血细胞综合征的临床表现

• DOI: 10.1002/ncn3.19
• 发表时间: 2013
• 期刊: Neurology and Clinical Neuroscience
• 影响因子: 0.4
• 作者: K. Koizumi;Y. Tsukada;D. Ito;S. Momoshima;S. Okamoto;N. Suzuki
• 通讯作者: N. Suzuki

Progressive motor deficit linked to ER stress in mutant seipin transgenic mice.

突变型 seipin 转基因小鼠的进行性运动缺陷与 ER 应激有关。

• 作者: Yagi T;Ito D;Nihei Y;Ishihara T;Suzuki N.
• 通讯作者: Suzuki N.

Drug-induced intracranial cystic lesion : a complication of antibiotic treatment via an Ommaya reservoir

药物引起的颅内囊性病变：通过 Ommaya 储库抗生素治疗的并发症

• 发表时间: 2013
• 期刊: Neurology and Clinical Neuroscience
• 影响因子: 0.4
• 作者: Yagi T;Osaka M;Ito D;Nihei Y;Ohira T;Takahashi S;Suzuki N
• 通讯作者: Suzuki N