Modest loss of peripheral axons, muscle atrophy and formation of brain inclusions in mice with targeted deletion of gigaxonin exon 1
Modest loss of peripheral axons, muscle atrophy and formation of brain inclusions in mice with targeted deletion of gigaxonin exon 1
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DOI：
10.1111/j.1471-4159.2008.05601.x
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发表时间：
2008-10-01
影响因子：
4.7
通讯作者：
Julien, Jean-Pierre
中科院分区：
文献类型：
--
作者：
Dequen, Florence;Bomont, Pascale;Julien, Jean-Pierre
gigaxonin 基因突变导致巨轴突神经病 (GAN)，这是一种与中间丝 (IF) 异常积累相关的进行性神经退行性疾病。 Gigaxonin 是新的 Cul3-E3-泛素连接酶家族的底物特异性接头，可促进其伙伴 MAP1B、MAP8 和微管蛋白辅因子 B 的蛋白酶体依赖性降解。在此，我们报告了定向删除 Gan 外显子 1 (Gan(Delta exon1;Delta exon1)) 的小鼠模型的生成。对 Gan(Delta exon1;Delta exon1) 小鼠的分析显示，神经系统中各种 IFs 蛋白的水平增加，并且大脑中存在 IFs 包涵体。尽管缺乏全长吉加松蛋白，Gan（Delta exon1；Delta exon1）小鼠并没有出现明显的神经表型和巨大的轴突，这让人想起人类 GAN 疾病。尽管如此，在 6 个月大时，Gan(Delta exon1;Delta exon1) 小鼠表现出适度的后肢肌肉萎缩，肌肉神经支配减少 10%，L5 腹根轴突损失 27%。这种新的小鼠模型应该提供一个有用的工具来测试 GAN 疾病的潜在治疗方法。
Mutations in the gigaxonin gene are responsible for giant axonal neuropathy (GAN), a progressive neurodegenerative disorder associated with abnormal accumulations of Intermediate Filaments (IFs). Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. Here, we report the generation of a mouse model with targeted deletion of Gan exon 1 (Gan(Delta exon1;Delta exon1)). Analyses of the Gan(Delta exon1;Delta exon1) mice revealed increased levels of various IFs proteins in the nervous system and the presence of IFs inclusion bodies in the brain. Despite deficiency of full length gigaxonin, the Gan(Delta exon1;Delta exon1) mice do not develop overt neurological phenotypes and giant axons reminiscent of the human GAN disease. Nonetheless, at 6 months of age the Gan(Delta exon1;Delta exon1) mice exhibit a modest hind limb muscle atrophy, a 10% decrease of muscle innervation and a 27% axonal loss in the L5 ventral roots. This new mouse model should provide a useful tool to test potential therapeutic approaches for GAN disease.