Muscle Atrophy and Motor Neuron Degeneration in Human NEDL1 Transgenic Mice

Lin Zhang,Tadayuki Koda,Akira Nakagawara,Seiki Haraguchi,Kenji Hashimoto

doi:10.1155/2011/831092

Abstract

Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease. Approximately 20% cases of familial ALS show the mutation in the superoxide dismutase-1 (SOD1) gene. We previously demonstrated that homologue to E6AP carboxyl terminus- (HECT-) type ubiquitin protein E3 ligase (NEDL1) physically bind to mutated SOD1 protein but not wild-type SOD1 and promote the degradation of mutated SOD1 protein through ubiquitin-mediated proteasome pathway. To further understand the role of NEDL1 involved in the pathogenesis of familial ALS, we generated transgenic mice with human NEDL1 cDNA. The transgenic mice with human NEDL1 expression showed motor dysfunctions in rotarod, hanging wire, and footprint pattern examination. Histological studies indicated degeneration of neurons in the lumbar spinal cord and muscle atrophy. The number of activated microglia in the spinal cord of transgenic mice was significantly higher than that of wild-type mice, suggesting that inflammation might be observed in the spinal cord of transgenic mice. In conclusion, these findings suggest that the human NEDL1 transgenic mice might develop ALS-like symptoms, showing signs of motor abnormalities, accompanied with significant reduction in muscle strength.

Highlights

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease is characterized by selective degeneration of motor neurons in the brain and spinal cord, resulting in progressive paralysis of limb, facial, and respiratory muscles and death within few years [1, 2]
We previously demonstrated that homologue to E6AP carboxyl terminus- (HECT-) type ubiquitin protein E3 ligase (NEDL1) physically bind to mutated superoxide dismutase-1 (SOD1) protein but not wildtype SOD1 and promote the degradation of mutated SOD1 protein through ubiquitin-mediated proteasome pathway
NEDL1 encodes HECT-type E3 ubiquitin ligase and is detected in human neuronal tissues, suggesting that NEDL1 might be involved in the regulation of the spontaneous regression of favorable neuroblastomas caused by apoptosis and/or neuronal differentiation [10]

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease is characterized by selective degeneration of motor neurons in the brain and spinal cord, resulting in progressive paralysis of limb, facial, and respiratory muscles and death within few years [1, 2]. The exact composition of such inclusions is incompletely understood, the protein identified so far includes ubiquitin [7], Cu/Zn superoxide dismutase 1 (SOD1) [8], Dorfin (a RING-finger-type E3 ubiquitin ligase) [9], and NEDL1 (NEDD4-like ubiquitin protein ligase-1), which has been identified as a novel gene expressed significantly at high levels in favorable neuroblastoma relative to unfavorable ones [10]. The property of NEDL1 protein is affected by binding with mutated SOD1 protein [10]. The biological role of NEDL1 involved in the pathogenesis of ALS is incompletely understood

Methods

Results

Conclusion