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- Alterations in lipid metabolism gene expression and abnormal lipid accumulation in fibroblast explants from giant axonal neuropathy patients

Giant Axonal Neuropathy (GAN) is a severe autosomal recessive disorder that affects both the central and peripheral nervous systems. The most prominent pathological feature of GAN is the large, focal accumulations of neuronal intermediate filaments (IFs) in distended axons [1]. Abnormal aggregations of IFs have also been found in astrocytes, endothelial cells, Schwann cells and cultured skin fibroblasts. Many GAN patients have frizzy hair that is distinctive from their parents. Chemical analysis of the hair has revealed a disruption of disulfide-bond formation in hair keratins [2]. Hence, a generalized disorganization of IFs has been proposed to be responsible for GAN [3].

Skin fibroblast explants collected from GAN patients have been used as a model to study the disease. Under normal culture conditions, a low percentage of GAN fibroblasts exhibit abnormal aggregation and bundling of vimentin IFs [4-7]. Upon various stimuli, such as low serum [5] or low doses of trypsin [6], the vimentin networks of GAN fibroblasts collapse and form aggregates. Moreover, the microtubule (MT)-depolymerizing agent nocodazole exerts different effects on normal and GAN fibroblasts. Although the IF networks of both types of fibroblasts collapse under nocodazole treatment, the aggregates formed in GAN cells are significantly more compact and dense [5]. Together, these data suggest that dysfunction of the GAN gene product might cause IFs to form aggregates that are harmful to cells.

A GAN gene has been identified and its product named gigaxonin, with twenty-three different mutations reported to date [8-10]. Gigaxonin is a member of the kelch repeat superfamily. It contains an N-terminal BTB/POZ (Broad-Complex, Tramtrack and Bric-a-brac/Poxvirus and Zinc-finger) domain and six C-terminal kelch motifs. MT-Associated Protein 1B (MAP1B), Tubulin Cofactor B (TBCB), and MT-Associated Protein 8 (MAP8 or MAP1S) have been identified as binding partners of gigaxonin in yeast two-hybrid screens [11-14]. Gigaxonin interacted with these proteins via the kelch repeats. The N-terminal BTB of gigaxonin could bind ubiquitin-activating enzyme E1, suggesting that gigaxonin functions as a scaffold protein in the ubiquitin-proteasome complex and mediates the degradation of MAP1B, TBCB and MAP8 [11]. Mutations in the GAN gene result in accumulation of these cytoskeletal proteins and eventual neurodegeneration.

Here, we report the characterization of two primary lines of cultured GAN fibroblasts carrying a total of three putative disease-linked GAN alleles. We compared the gene expression profiles of the GAN fibroblasts to those of normal fibroblasts. We found that the expression of lipid metabolism genes was perturbed in GAN fibroblasts most dramatically. In addition to changes in the expression levels of lipid metabolism genes, we also discovered an increase in the number of neutral lipid droplets in GAN cells. These data suggest that defects in lipid metabolism may contribute to the pathogenesis of GAN.

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