Explaining intermediate filament accumulation in giant axonal neuropathy

Abstract

Giant axonal neuropathy (GAN)¹ is a rare autosomal recessive neurological disorder caused by mutations in the GAN gene that encodes gigaxonin, a member of the BTB/Kelch family of E3 ligase adaptor proteins.¹ This disease is characterized by the aggregation of Intermediate Filaments (IF)—cytoskeletal elements that play important roles in cell physiology including the regulation of cell shape, motility, mechanics and intra-cellular signaling. Although a range of cell types are affected in GAN, neurons display the most severe pathology, with neuronal intermediate filament accumulation and aggregation; this in turn causes axonal swellings or “giant axons.” A mechanistic understanding of GAN IF pathology has eluded researchers for many years. In a recent study¹ we demonstrate that the normal function of gigaxonin is to regulate the degradation of IF proteins via the proteasome. Our findings present the first direct link between GAN mutations and IF pathology; moreover, given the importance of IF aggregations in a wide range of disease conditions, our findings could have wider ramifications.

Keywords: :

• giant axonal neuropathy
• gigaxonin
• intermediate filaments
• neurofilaments
• vimentin
• BTB/Kelch

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Disclosure of Potential Conflicts of Interest

No potential conflict of interest was disclosed.

Acknowledgments

We acknowledge the contributions of all the co-authors of our recent JCI publication. We thank Lori Sames and the Hannah’s Hope Fund for providing support to enable us to carry out this research as well as NIH 1P01GM096971–01 to R.D.G. and NIH R01 NS062051 to P.O. We thank Dale Shumaker for help with the artwork.