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

Shinsuke Ishigaki, Jun ichi Niwa, Shin ichi Yamada, Miho Takahashi, Takashi Ito, Jun Sone, Manabu Doyu, Fumihiko Urano, Gen Sobue

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

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 (DorfinWT). One of the Dorfin-CHIP chimeric proteins, Dorfin-CHIPL, ubiquitylated mutant SOD1 more effectively than did DorfinWT and CHIP in vivo, and degraded mutant SOD1 protein more rapidly than DorfinWT does. Furthermore, Dorfin-CHIPL rescued neuronal cells from mutant SOD1-associated toxicity and reduced the aggresome formation induced by mutant SOD1 more effectively than did DorfinWT.

Original languageEnglish
Pages (from-to)331-341
Number of pages11
JournalNeurobiology of Disease
Volume25
Issue number2
DOIs
StatePublished - Feb 2007

Keywords

  • ALS
  • CHIP
  • Dorfin
  • Neurodegeneration
  • SOD1
  • Ubiquitin-proteasome system

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