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Human Molecular Genetics Advance Access published online on March 24, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl069
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received January 24, 2006
Revised March 15, 2006
Accepted March 15, 2006

Article

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 1, Wei Wang 1, Angela Valle 1, Chengbiao Wu 1, Timothy Nardine 1, Bianxiao Cui 2, Jing Yi 3, Anne Taylor 4, Noo Li Jeon 4, Steven Chu 2, Yuen So 1, Hannes Vogel 5, Ravi Tolwani 6, William Mobley 1, and Yanmin Yang 1 *

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

* To whom correspondence should be addressed.
Yanmin Yang, E-mail: yanmin.yang{at}stanford.edu


  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 that 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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