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

UMMS Affiliation

Program in Gene Function and Expression; Program in Molecular Medicine

Publication Date


Document Type



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


Genetics and Genomics


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).

DOI of Published Version



Neurobiol Dis. 2007 Feb;25(2):331-41. Epub 2006 Dec 6. Link to article on publisher's site

Journal/Book/Conference Title

Neurobiology of disease

Related Resources

Link to Article in PubMed

PubMed ID