Giant axonal neuropathy–associated gigaxonin mutations impair intermediate filament protein degradation
Autor: | Alessandro Didonna, Saleemulla Mahammad, Boris Grin, Jean-Pierre Julien, Edward R. Kuczmarski, Pascale Bomont, S. N. Prasanna Murthy, Robert D. Goldman, Rodolphe Perrot, Eitan Israeli, Puneet Opal |
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Rok vydání: | 2013 |
Předmět: |
Neurofilament
Leupeptins Ubiquitin-Protein Ligases Enzyme-Linked Immunosorbent Assay Mice Transgenic Vimentin medicine.disease_cause Mice Intermediate Filament Proteins medicine Animals Humans Intermediate Filament Protein RNA Messenger Intermediate filament Cytoskeleton Giant axonal neuropathy Neurons Mutation biology Gigaxonin Peripherin Sequence Analysis DNA General Medicine Fibroblasts medicine.disease Molecular biology Cell biology Cytoskeletal Proteins HEK293 Cells Microscopy Fluorescence Giant Axonal Neuropathy NIH 3T3 Cells biology.protein Proteasome Inhibitors Research Article |
Zdroj: | Journal of Clinical Investigation. 123:1964-1975 |
ISSN: | 0021-9738 |
Popis: | 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. |
Databáze: | OpenAIRE |
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