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

Jun Sone; Jun-ichi Niwa; Kaori Kawai; Shinsuke Ishigaki; Shin-ichi Yamada; Hiroaki Adachi; Masahisa Katsuno; Fumiaki Tanaka; Manabu Doyu; Gen Sobue

doi:10.1002/jnr.22175

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

J Neurosci Res. 2010 Jan;88(1):123-35. doi: 10.1002/jnr.22175.

Authors

Jun Sone¹, Jun-ichi Niwa, Kaori Kawai, Shinsuke Ishigaki, Shin-ichi Yamada, Hiroaki Adachi, Masahisa Katsuno, Fumiaki Tanaka, Manabu Doyu, Gen Sobue

Affiliation

¹ Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

PMID: 19610091
DOI: 10.1002/jnr.22175

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
Gene Dosage / genetics
Immunohistochemistry
Immunoprecipitation
Kaplan-Meier Estimate
Mice
Mice, Transgenic
Motor Skills / physiology
Nerve Degeneration / genetics
Nerve Degeneration / metabolism
Nerve Degeneration / pathology
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-Protein Ligases / genetics*
Ubiquitin-Protein Ligases / metabolism

Substances

Superoxide Dismutase
Ubiquitin-Protein Ligases