Ding Jianqing, Allen Elizabeth, Wang Wei, Valle Angela, Wu Chengbiao, Nardine Timothy, Cui Bianxiao, Yi Jing, Taylor Anne, Jeon Noo Li, Chu Steven, So Yuen, Vogel Hannes, Tolwani Ravi, Mobley William, Yang Yanmin
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 1201 Welch Road, CA 94305-5489, USA.
Hum Mol Genet. 2006 May 1;15(9):1451-63. doi: 10.1093/hmg/ddl069. Epub 2006 Mar 24.
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.
在常染色体隐性疾病——巨大轴索性神经病（GAN）中发现了Gigaxonin基因突变。为了了解Gigaxonin功能的破坏如何导致神经退行性变，我们使用传统基因靶向方法在小鼠中消除了该基因的表达。GAN基因敲除小鼠中出现的进行性神经表型和病理损伤重现了人类GAN的特征。Gigaxonin的破坏导致泛素-蛋白酶体系统受损，导致一种新型微管相关蛋白MAP8在基因敲除突变体中大量积累。积累的MAP8改变了微管网络，将动力蛋白捕获在不溶性结构中，并导致野生型培养神经元死亡，这重现了GAN基因敲除突变体中发生的过程。体外试验证明轴突运输存在缺陷，GAN基因敲除神经元中的囊泡积累也支持了这一点。我们认为轴突运输障碍可能是积累的有毒MAP8蛋白的有害后果。
