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. 2006 May 1;15(9):1451-63.
doi: 10.1093/hmg/ddl069. Epub 2006 Mar 24.

Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport

Jianqing Ding  1 , Elizabeth Allen, Wei Wang, Angela Valle, Chengbiao Wu, Timothy Nardine, Bianxiao Cui, Jing Yi, Anne Taylor, Noo Li Jeon, Steven Chu, Yuen So, Hannes Vogel, Ravi Tolwani, William Mobley, Yanmin Yang
Affiliations

Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport

Jianqing Ding et al. Hum Mol Genet. .

Abstract

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.

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