Dorfin ameliorates phenotypes in a transgenic mouse model of amyotrophic lateral sclerosis

• Published in: Journal of neuroscience research 2010-01, Vol.88 (1), p.123-135
• Main Authors: Sone, Jun, Niwa, Jun-ichi, Kawai, Kaori, Ishigaki, Shinsuke, Yamada, Shin-ichi, Adachi, Hiroaki, Katsuno, Masahisa, Tanaka, Fumiaki, Doyu, Manabu, Sobue, Gen
• Format: Article
• Language: English
• Subjects: ALS; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - physiopathology; Analysis of Variance; Animals; Astrocytes - metabolism; Astrocytes - pathology; Blotting, Western; Disease Models, Animal; Dorfin; G93A mutant SOD1; Gene Dosage - genetics; Immunohistochemistry; Immunoprecipitation; Kaplan-Meier Estimate; Mice; Mice, Transgenic; Motor Skills - physiology; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; neurodegeneration; Neurons - metabolism; Neurons - pathology; Phenotype; Rotarod Performance Test; Spinal Cord - metabolism; Spinal Cord - pathology; Spinal Cord - physiopathology; Spinal Nerve Roots - metabolism; Spinal Nerve Roots - pathology; Spinal Nerve Roots - physiopathology; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; ubiquitin ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0360-4012; 1097-4547; 1097-4547
• DOI: 10.1002/jnr.22175

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by progressive motor neuron degeneration and leads to death within a few years of diagnosis. One of the pathogenic mechanisms of ALS is proposed to be a dysfunction in the protein quality‐control machinery. Dorfin has been identified as a ubiquitin ligase (E3) that recognizes and ubiquitinates mutant SOD1 proteins, thereby accelerating their degradation and reducing their cellular toxicity. We examined the effects of human Dorfin overexpression in G93A mutant SOD1 transgenic mice, a mouse model of familial ALS. In addition to causing a decrease in the amount of mutant SOD1 protein in the spinal cord, Dorfin overexpression ameliorated neurological phenotypes and motor neuron degeneration. Our results indicate that Dorfin overexpression or the activation or induction of E3 may be a therapeutic avenue for mutant SOD1‐associated ALS. © 2009 Wiley‐Liss, Inc.