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

Neurobiology of Disease

卷:25

Jun-ichi Niwa¹  Jun Sone²  Shinsuke Ishigaki²  Takashi Ito²  Shin-ichi Yamada²  Manabu Doyu²  Fumihiko Urano²  Miho Takahashi²  Gen Sobue³ 

[1] Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA;

[2] Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8500, Japan;

关键词: Dorfin;    ALS;    SOD1;    CHIP;    Neurodegeneration;    Ubiquitin–proteasome system;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown