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Generation of novel animal models for amyofrophic lateral sclerosis and studies on the molecular mechanisms underlying motor dysfunction

肌萎缩侧索硬化症新型动物模型的建立及运动功能障碍分子机制的研究

基本信息

批准号：
17300121
负责人：
HADANO Shinji
金额：
$ 10.3万
依托单位：
Tokai University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

Loss of function mutations in ALS2 account for a number of juvenile/infantile recessive motor neuron diseases, indicating that its gene product, ALS2, plays a crucial role in maintenance and survival for a subset of neurons. However, the normal physiological role of ALS2 in vivo and the molecular mechanisms underlying motor dysfunction are still unknown. To address these issues, we generated several lines of ALS2 transgenic mice and congenic lines of the Als2 knock-out (KO) mice in this study. Neither loss nor overexpression of ALS2 solely produced a severe disease phenotype in mice. However, when the Als2-KO mice was crossed with the SOD1R46R mouse line expressing familial ALS-linked SOD1H46R Als2-KO ; SOD1^<H46R>mice showed a much earlier motor dysfunction as well as a shorter life span than SODIH46R mice, suggesting that ALS2 plays a role in the onset and/or progression of motor neuron disease associated with mutant SOD1 in vivo. Next, to elucidate the neuronal ALS2 functions, we in … More vestigated cellular phenotypes of ALS2-deficient primary cultured neurons. ALS2 deficiency resulted not only in the delay of axon outgrowth in hippocampal neurons, but also in a decreased level of the macropinocytic activity in cortical neurons, suggesting that ALS2 acts as a modulator in neuronal differentiation and/or development through regulation of membrane dynamics. Finally, we investigated the molecular features of ALS2CL, a novel ALS2 homolog, and its functional relationship with ALS2. It was revealed that ALS2CL was a novel ALS2-interacting protein and was implicated in ALS2-mediated endosome dynamics. Collectively, our newly generated animals overexpressing and/or deleting ALS2 should provide invaluable research tools with which to understand the interplay between ALS2-mediated endosomal dynamics and the long-term viability of motor neurons in vivo. Further characterization of these mice will also clarify the implication of the ALS2-mediated neuronal functions in the pathogenesis for mutant SOD1-linkedALS. Less

Als2的功能突变缺失是许多青少年/婴儿隐性运动神经元病的原因，这表明其基因产物als2在维持和存活一小部分神经元方面发挥着关键作用。然而，als2在体内的正常生理作用和运动功能障碍的分子机制仍不清楚。为了解决这些问题，我们在本研究中建立了几个als2转基因小鼠品系和als2基因敲除(KO)小鼠的同源品系。在小鼠中，als2的缺失或过表达都不会单独产生严重的疾病表型。然而，当als2-KO小鼠与表达家族性肌萎缩侧索硬化症连锁SOD1H46R的SOD1R46R小鼠品系杂交时，als2-KO；SOD1H46R；SOD1H46R&GT；小鼠表现出比SODIH46R小鼠更早的运动功能障碍和更短的寿命，这表明als2在体内与突变SOD1相关的运动神经元疾病的发生和/或发展中发挥了作用。接下来，为了阐明神经元als2的功能，我们在…更多研究als2缺陷的原代培养神经元的细胞表型。ALS2缺乏症不仅导致海马神经元轴突生长延迟，而且皮质神经元的巨噬细胞活性降低，提示ALS2通过膜动力学调控在神经元分化和/或发育过程中起调节作用。最后，我们研究了一种新的ALS2同系物ALS2CL的分子特征及其与ALS2的功能关系。研究表明，ALS2CL是一种新的ALS2相互作用蛋白，与ALS2介导的内体动力学有关。总而言之，我们新产生的动物过表达和/或缺失als2应该提供宝贵的研究工具，用来了解als2介导的内体动力学和体内运动神经元长期存活之间的相互作用。这些小鼠的进一步特征也将阐明als2介导的神经元功能在突变的SOD1连锁ALS发病机制中的意义。较少

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ALS2 is a novel Rac1-regulated Macropinosomal Rab5GEF that mediates interconnection between distinct endocytic pathways

ALS2 是一种新型 Rac1 调节的巨胞苷体 Rab5GEF，可介导不同内吞途径之间的互连

DOI：
发表时间：
2006
期刊：
Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 7巻(suppl 1)
影响因子：
0
作者：
Tomoyuki Yoshida;Ikuo Tomioka;Takako Nagahara;Trudy_Holyst;Motoshi Sawada;Paulette Hayes;Vivian Gama;Misako Okuno;Yohong Chen;Yasuyuki Abe;Tadashi Kanouchi;Hiroshi Sasada;Demin Wang;Takanori Yokota;Shigemi Matsuyama;Eimei Sato;鈴木恭子;大友麻子;國田竜太
通讯作者：
國田竜太

Purification and functional analyses of ALS2 and its homologue

ALS2及其同源物的纯化和功能分析

DOI：
发表时间：
2005
期刊：
Methods in Enzymology 403
影响因子：
0
作者：
Hadano;S.;et. al.;泰野伸二;Asako Otomo;Ryota Kunita;Shinji Hadano;Yoshinori Okada;Shinji Hadano
通讯作者：
Shinji Hadano

The Rab5 activator ALS2/alsin acts as a novel Racl effector via Racl-activated macropinocytosis

Rab5 激活剂 ALS2/alsin 通过 Racl 激活的巨胞饮作用充当新型 Racl 效应子