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NEUROBIOL AGING:: 利用线虫构建新型肌萎缩性侧索硬化症(ALS)模型

来源:生物谷 2013-11-19 11:56

2013年11月19日 讯 /生物谷BIOON/ --2013年10月14日,知名神经生物学期刊《老年神经生物学》(Neurobiology of Aging)在线发表了中科院上海生命科学研究院/上海交通大学医学院健康科学研究所乐卫东研究组的最新研究成果"Human superoxide dismutase 1 overexpression in motor neurons of Caenorhabditis elegans causes axon guidance defect and neurodegeneration",利用线虫构建了新型肌萎缩性侧索硬化症(ALS)模型。

ALS是一种运动神经退行性疾病,病理表现为脊髓运动神经元大量死亡。研究证明,铜锌超氧化物歧化酶(SOD1)的大量积聚可以导致运动神经元的死亡,而大概有20%的家族型ALS病人存在多种突变形式的SOD1。虽然SOD1的错误折叠与聚集导致运动神经元损伤,但是其具体的分子学机制目前并不明朗。

在该研究中,健康所博士研究生李佳在乐卫东研究员的指导下,通过向线虫运动神经元里特异地过表达人源的野生型SOD1和突变型SOD1(G93A),成功再现了ALS的多种病理表现,包括年龄依赖性的运动障碍,运动神经元的死亡,以及SOD1的大量聚集和包涵体的形成。同时他们还发现,在构建的ALS转基因线虫的发育中,神经元的轴突导向也受到了损伤。

该项工作首次在线虫的运动神经元特异地过表达SOD1以构建新型的ALS模型,并成功的重现了ALS的轴突发育损伤以及成体后神经元的退行性死亡过程。这为进一步研究SOD1对ALS的致病机制提供了新的平台以及研究思路。

该课题研究得到了国家自然科学基金委和中国科学院等经费资助。(生物谷 Bioon.com)

生物谷推荐英文摘要:


Neurobiology of Aging  doi: 10.1016/j.neurobiolaging.2013.09.003.

Human superoxide dismutase 1 overexpression in motor neurons of Caenorhabditis elegans causes axon guidance defect and neurodegeneration.

Li J, Li T, Zhang X, Tang Y, Yang J, Le W.

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.

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