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Human Molecular Genetics Advance Access originally published online on March 24, 2006
Human Molecular Genetics 2006 15(9):1451-1463; doi:10.1093/hmg/ddl069
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Jianqing Ding1,{dagger}, Elizabeth Allen1,{dagger}, Wei Wang1, Angela Valle1, Chengbiao Wu1, Timothy Nardine1, Bianxiao Cui4, Jing Yi5, Anne Taylor6, Noo Li Jeon6, Steven Chu4, Yuen So1, Hannes Vogel3, Ravi Tolwani2, William Mobley1 and Yanmin Yang1,*

1Department of Neurology and Neurological Sciences, 2Department of Comparative Medicine, 3Department of Pathology, Stanford University School of Medicine 1201 Welch Road, Stanford, CA 94305-5489, USA, 4Department of Physics, Stanford University, Stanford, CA, USA, 5Department of Cell Biology, Shanghai Second Medical University, Shanghai, China and 6Department of Biomedical Engineering, University of California, Irvine, CA, USA

* To whom correspondence should be addressed. Tel: +1 6507361032; Fax: +1 6504986262; Email: yanmin.yang{at}stanford.edu

Received January 24, 2006; Accepted March 15, 2006

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.

{dagger} The first two authors contributed equally to the work.


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