Tangled


Giant axonal neuropathy (GAN) is a rare genetic disorder that causes central and peripheral nervous system neuropathy at a young age. This neuropathy is caused by mutations in the gene encoding gigaxonin and is associated with aggregates of intermediate filaments in neurons and other cell types, such as fibroblasts.  These abnormal aggregates have long been known to involve numerous classes of cytoskeletal intermediate filaments, but the mechanisms underlying aggregate formation have been unclear.  Saleemulla Mahammad and colleagues uncovered how mutations in gigaxonin contribute to aggregate formation. They demonstrated that gigaxonin regulates the degradation of peripherin, neurofilament light chain and vimentin intermediate filaments in a proteasome-dependent manner. These findings reveal the importance of gigaxonin in regulating cytoskeletal intermediate filaments and explain how mutations in gigaxonin cause aggregate formation in GAN.  In the cover image from the May issue of the JCI, an epidermal fibroblast from a GAN patient exhibits large aggregates of vimentin intermediate filaments (green); DAPI staining indicates the nucleus (blue).

Published May 1, 2013, by Jillian Hurst

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Giant axonal neuropathy–associated gigaxonin mutations impair intermediate filament protein degradation
Saleemulla Mahammad, … , Puneet Opal, Robert D. Goldman
Saleemulla Mahammad, … , Puneet Opal, Robert D. Goldman
Published April 15, 2013
Citation Information: J Clin Invest. 2013;123(5):1964-1975. https://doi.org/10.1172/JCI66387.
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Research Article Neuroscience

Giant axonal neuropathy–associated gigaxonin mutations impair intermediate filament protein degradation

Abstract

Giant axonal neuropathy (GAN) is an early-onset neurological disorder caused by mutations in the GAN gene (encoding for gigaxonin), which is predicted to be an E3 ligase adaptor. In GAN, aggregates of intermediate filaments (IFs) represent the main pathological feature detected in neurons and other cell types, including patients’ dermal fibroblasts. The molecular mechanism by which these mutations cause IFs to aggregate is unknown. Using fibroblasts from patients and normal individuals, as well as Gan–/– mice, we demonstrated that gigaxonin was responsible for the degradation of vimentin IFs. Gigaxonin was similarly involved in the degradation of peripherin and neurofilament IF proteins in neurons. Furthermore, proteasome inhibition by MG-132 reversed the clearance of IF proteins in cells overexpressing gigaxonin, demonstrating the involvement of the proteasomal degradation pathway. Together, these findings identify gigaxonin as a major factor in the degradation of cytoskeletal IFs and provide an explanation for IF aggregate accumulation, the subcellular hallmark of this devastating human disease.

Authors

Saleemulla Mahammad, S.N. Prasanna Murthy, Alessandro Didonna, Boris Grin, Eitan Israeli, Rodolphe Perrot, Pascale Bomont, Jean-Pierre Julien, Edward Kuczmarski, Puneet Opal, Robert D. Goldman

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