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Dorfin-CHIP chimeric proteins potently ubiquitylate and degrade familial ALS-related mutant SOD1 proteins and reduce their cellular toxicity.

The ubiquitin-proteasome system (UPS) is involved in the pathogenetic mechanisms of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Dorfin is a ubiquitin ligase (E3) that degrades mutant SOD1 proteins, which are responsible for familial ALS. Although Dorfin has potential as an anti-ALS molecule, its life in cells is short. To improve its stability and enhance its E3 activity, we developed chimeric proteins containing the substrate-binding hydrophobic portion of Dorfin and the U-box domain of the carboxyl terminus of Hsc70-interacting protein (CHIP), which has strong E3 activity through the U-box domain. All the Dorfin-CHIP chimeric proteins were more stable in cells than was wild-type Dorfin (Dorfin(WT)). One of the Dorfin-CHIP chimeric proteins, Dorfin-CHIP(L), ubiquitylated mutant SOD1 more effectively than did Dorfin(WT) and CHIP in vivo, and degraded mutant SOD1 protein more rapidly than Dorfin(WT) does. Furthermore, Dorfin-CHIP(L) rescued neuronal cells from mutant SOD1-associated toxicity and reduced the aggresome formation induced by mutant SOD1 more effectively than did Dorfin(WT).

Pubmed ID: 17157513

Authors

  • Ishigaki S
  • Niwa J
  • Yamada S
  • Takahashi M
  • Ito T
  • Sone J
  • Doyu M
  • Urano F
  • Sobue G

Journal

Neurobiology of disease

Publication Data

February 26, 2007

Associated Grants

None

Mesh Terms

  • Amyotrophic Lateral Sclerosis
  • Animals
  • Cell Death
  • Cell Line
  • DNA-Binding Proteins
  • Humans
  • Mice
  • Mutation
  • Nerve Degeneration
  • Neurotoxins
  • Proteasome Endopeptidase Complex
  • Recombinant Fusion Proteins
  • Superoxide Dismutase
  • Ubiquitin
  • Ubiquitin-Protein Ligases