title: Human superoxide dismutase 1 overexpression in motor neurons of Caenorhabditis elegans causes axon guidance defect and neurodegeneration.
abstract: Strong evidence indicates that mutant Cu, Zn-superoxide dismutase 1 (SOD1) exerts toxic effect on motor neurons in amyotrophic lateral sclerosis (ALS). However, the nature of mutant SOD1-mediated motor neuron degeneration is poorly understood. To provide new insight into the mechanism by which mutant SOD1 induces motor neuron injury, we developed novel Caenorhabditis elegans models of ALS. Expression of human wild type or G93A SOD1 specifically in motor neurons of C. elegans caused progressive locomotion defect and paralytic phenotype, which recapitulate some characteristic features of ALS including age-dependent motor dysfunction and degeneration of motor neurons associated with SOD1 aggregation. In addition, the motor neuron loss is independent of cell death protein 3 (CED-3)/cell death protein 4 (CED-4) caspase pathway. We also found that before motor neurons began to die in adulthood, axon guidance defect of motor neuron appeared during the development stages. When green fluorescent protein (GFP)-tagged proteins related to axon guidance were examined in motor neurons, a significantly decreased density and number of GFP-tagged puncta were observed in the transgenic worms. Our models mimic axon developmental defect and the adult-onset degeneration of motor neurons in ALS. Using this model, we uncovered the cell-autonomous damage caused by human SOD1 to motor neurons in vivo, and provided a new insight into the developmental defect mechanism that may contribute to motor neuron degeneration in ALS.
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Yang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China; 1st Affiliated Hospital, Dalian Medical University, Dalian, China. Electronic address: weidongl@bcm.edu.
authors.forename: Weidong
authors.initials: W
authors.lastname: Le
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001369:Axons / Q000473:pathology; D017173:Caenorhabditis elegans; D004195:Disease Models, Animal; D006801:Humans; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology*; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics / Q000633:toxicity*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; Axon guidance defect; Caenorhabditis elegans; Caspase pathway; Cu, Zn-superoxide dismutase; Motor neuron degeneration