Gigaxonin interacts with tubulin folding cofactor B and controls its degradation through the ubiquitin-proteasome pathway

Curr Biol. 2005 Nov 22;15(22):2050-5. doi: 10.1016/j.cub.2005.10.052.

Abstract

Gigaxonin is mutated in human giant axonal neuropathy (GAN), an autosomal recessive neurodegenerative disorder. The presence of generalized cytoskeletal abnormalities , including few microtubules and accumulated intermediate filaments (IFs), in GAN suggests an essential role of gigaxonin in cytoskeletal organization and dynamics. However, the molecular mechanisms underlying the cytoskeletal pathology remain to be elucidated. Over the years, the ubiquitin-proteasome system (UPS) of intracellular protein degradation has been implicated in the control of many fundamental cellular processes. Defects in this system seem to be directly linked to the development of human diseases, including cancers and neurodegenerative diseases . Here, we show that gigaxonin controls protein degradation of tubulin folding cofactor B (TBCB) , a function disrupted by GAN-associated mutations. The substantial TBCB protein accumulation caused by impaired UPS may be a causative factor of cytoskeletal pathology in GAN. Our study provides important insight into pathogenesis of neurodegenerative diseases associated with cytoskeletal abnormalities.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Cytoskeleton / physiology*
  • Humans
  • Microscopy, Fluorescence
  • Microtubule-Associated Proteins / metabolism*
  • Molecular Chaperones
  • Mutation / genetics
  • Protein Structure, Tertiary
  • Two-Hybrid System Techniques
  • Ubiquitin-Protein Ligase Complexes / metabolism*

Substances

  • Cytoskeletal Proteins
  • GAN protein, human
  • Microtubule-Associated Proteins
  • Molecular Chaperones
  • tubulin cofactor B, human
  • Ubiquitin-Protein Ligase Complexes