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).
Giant axonal neuropathy (GAN) is an early-onset neurological disorder caused by mutations in the
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