Journal Article

Gigaxonin controls vimentin organization through a tubulin chaperone-independent pathway

Don W. Cleveland, Koji Yamanaka and Pascale Bomont

in Human Molecular Genetics

Volume 18, issue 8, pages 1384-1394
Published in print April 2009 | ISSN: 0964-6906
Published online January 2009 | e-ISSN: 1460-2083 | DOI:
Gigaxonin controls vimentin organization through a tubulin chaperone-independent pathway

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Gigaxonin mutations cause the fatal human neurodegenerative disorder giant axonal neuropathy (GAN). Broad deterioration of the nervous system in GAN patients is accompanied by massive disorganization of intermediate filaments (IFs) both in neurons and many non-neuronal cells. With newly developed antibodies, gigaxonin is now shown to be expressed at extremely low levels throughout the nervous system. In lymphoblast cell lines derived from severe and mild forms of GAN, mutations in gigaxonin are shown to yield highly unstable proteins, thereby permitting a rapid diagnostic test for the spectrum of GAN mutations as an alternative to invasive nerve biopsy or systematic sequencing of the GAN gene. Gigaxonin has been proposed as a substrate adaptor for an E3 ubiquitin ligase, which affects proteasome-dependent degradation of microtubule-related proteins including MAP1B, MAP8 and the tubulin folding chaperone TBCB. We demonstrate that, unlike its counterpart TBCE, TBCB only moderately destabilizes microtubules. Neither TBCB abundance nor microtubule organization or densities are altered in GAN mutant fibroblasts, thus demonstrating that altered TBCB levels are not primary determinants of IF disorganization in GAN. Characteristic GAN mutant-induced ovoid aggregates of vimentin are not produced in normal fibroblasts after disrupting microtubule assembly, either by TBCE overexpression or depolymerizing drugs. Thus, IF disorganization in GAN fibroblasts is independent of TBCB and microtubule loss and must be regulated by a yet unidentified mechanism.

Journal Article.  5476 words.  Illustrated.

Subjects: Genetics and Genomics

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