benzyloxycarbonylleucyl-leucyl-leucine-aldehyde and Giant-Axonal-Neuropathy

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.

Topics: Animals; Cytoskeletal Proteins; Cytoskeleton; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Giant Axonal Neuropathy; HEK293 Cells; Humans; Intermediate Filament Proteins; Leupeptins; Mice; Mice, Transgenic; Microscopy, Fluorescence; Mutation; Neurons; NIH 3T3 Cells; Proteasome Inhibitors; RNA, Messenger; Sequence Analysis, DNA; Ubiquitin-Protein Ligases; Vimentin