Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport
Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport
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DOI：
10.1093/hmg/ddl069
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发表时间：
2006-05-01
影响因子：
3.5
通讯作者：
Yang, YM
中科院分区：
文献类型：
--
作者：
Ding, JQ;Allen, E;Yang, YM
巨轴突神经病（GAN）是一种常染色体隐性遗传病，在GIGAXONIN中发现了突变。为了了解gigaxonin功能的破坏如何导致神经退行性变，我们使用传统的基因靶向方法消除了小鼠中的基因表达。在GAN缺失小鼠中发展的进行性神经表型和病理学病变概括了人类GAN的特征。破坏gigaxonin的结果在一个受损的泛素-蛋白酶体系统，导致大量积累的一种新的微管相关蛋白，MAP 8，在无效突变体。积累的MAP 8改变微管网络，将动力蛋白马达蛋白捕获在不溶性结构中，并导致培养的野生型神经元中的神经元死亡，这复制了GAN无效突变体中发生的过程。体外试验证明了轴突运输缺陷，并且GAN无效神经元中的囊泡积聚也支持了这一点。我们建议，轴突运输障碍可能是一个有害的后果积累，有毒的MAP 8蛋白。
Mutations in gigaxonin were identified in giant axonal neuropathy (GAN), an autosomal recessive disorder. To understand how disruption of gigaxonin's function leads to neurodegeneration, we ablated the gene expression in mice using traditional gene targeting approach. Progressive neurological phenotypes and pathological lesions that developed in the GAN null mice recapitulate characteristic human GAN features. The disruption of gigaxonin results in an impaired ubiquitin-proteasome system leading to a substantial accumulation of a novel microtubule-associated protein, MAP8, in the null mutants. Accumulated MAP8 alters the microtubule network, traps dynein motor protein in insoluble structures and leads to neuronal death in cultured wild-type neurons, which replicates the process occurring in GAN null mutants. Defective axonal transport is evidenced by the in vitro assays and is supported by vesicular accumulation in the GAN null neurons. We propose that the axonal transport impairment may be a deleterious consequence of accumulated, toxic MAP8 protein.