Gigaxonin regulates vimentin structure by modulating the Ras pathway through the degradation of galectin‐1 (796.11)

Abstract

Giant axonal neuropathy (GAN) is a progressive neurodegenerative disorder characterized by intermediate filament abnormalities. GAN is caused by a loss of gigaxonin (Giga), which functions as an E3 ligase adaptor in the ubiquitin proteasome system. A previous bioinformatics study showed that levels of galectin‐1 (Gal‐1), which stabilizes activated Ras, were significantly increased in GAN cells. We tested the hypothesis that Giga regulates intermediate filament structure via Gal‐1 using GAN fibroblasts. We showed that Giga controls the degradation of Gal‐1, as restoring Giga decreased Gal‐1 protein levels and rescued the vimentin structure in GAN fibroblasts. In addition, directly decreasing the levels of Gal‐1 using siRNA rescued the vimentin structure, which was quantified using the absence of vimentin in the GAN cell periphery, termed vimentin free zones (VFZs). VFZs were observed in 82.5% of control GAN cells, and after siRNA inhibition of Gal‐1, only 20.5% of cells displayed the same phenotype. Furthermore, disruption of downstream Ras signaling rescued the GAN phenotype, as siRNA directed against H‐Ras and MEK1/2 decreased the percentage of cells with VFZs to 37.6% and 43.7% respectively. These results show that accumulation of Gal‐1 from the loss of Giga activates the Ras pathway leading to the abnormal vimentin structure in GAN cells and that inhibition of Ras signaling may be therapeutic option for GAN.