脊髓小脑共济失调致病基因X在果蝇中的异常表型探究
发布时间：2018-09-05 19:06
【摘要】：脊髓小脑性共济失调(SCA, spinocerebellar ataxia)是一类遗传性神经退行性疾病,目前发现有30余种SCA亚型(DRPLA, SCA1-8,10-23,25-31)。多数SCA亚型由于致病基因内CAG重复片段异常扩增,导致多聚谷氨酰胺链的突变蛋白在细胞核内聚集形成核内包涵体。SCA主要临床特征表现为脊髓和小脑以及脊神经、脑神经、交感神经等组织的病变。 合作单位通过全外显子组测序在一个常染色体隐性遗传的SCA家系中发现了新的致病基因X(由于文章尚未发表,该基因暂用X代替,之后M、A、B、C同)。X基因编码的蛋白是近年新发现的类泛素化激活酶(E1),激活M基因编码的类泛素蛋白。已发现的M的类泛素结合酶(E2)为A,类泛素连接酶(E3)为B以及已知的M作用底物C。在线虫中的研究发现该类泛素化修饰系统参与线虫生殖,发育以及对有害环境因素的抵抗力。在小鼠模型的相关研究中,X基因敲除小鼠胚胎致死。 目的：X基因在生物体中发挥的功能,以及X导致SCA的发病机制有待进一步被研究阐明。通过对X基因的果蝇模型进行研究,我们发现其能很好地模拟SCA疾病发生。 方法：利用果蝇UAS-GAL4系统诱导X基因以及M类泛素化修饰通路中其他重要分子的knockdown,观察果蝇异常表型。 结果：1)全身表达GAL4诱导X基因的低表达能引起静息时果蝇翅膀呈稳定单翅或双翅垂直展开的表型。25℃时Da-Gal4UAS-X RNAi雄果蝇表现率为33.5%,且该果蝇的飞行和爬行能力明显降低,其寿命也明显缩短；2)在X基因knockdown果蝇羽化后第三天,其胸部肌肉切片中未见肌肉组织形态和结构的明显异常；3)X基因knockdown的果蝇三龄幼虫腹侧纵向4号肌肉和13/12号肌肉上神经肌肉接头数目减少；4)全身性knockdown M和A基因,果蝇表现出与X基因knockdown相似表型,25℃时Da-Gal4UAS-M RNAi以及Da-Gal4UAS-A RNAi雄果蝇表现率分别为71.3%和37.8%。 结论：综上所述,通过在果蝇模型中研究发现X基因knockdown很好地模拟SCA的发生。由于X基因参与M类泛素化修饰通路中的关键分子M和Aknockdown后能出现X基因knockdown后相似的果蝇表型,这些现象揭示该通路在SCA疾病发生中起到重要的作用。
[Abstract]:Spinal cerebellar ataxia (SCA, spinocerebellar ataxia) is a kind of hereditary neurodegenerative disease. More than 30 SCA subtypes (DRPLA, SCA1-8,10-23,25-31) have been found. Due to abnormal amplification of CAG repeats in most SCA subtypes, polyglutamine chain mutated proteins form intranuclear inclusions in the nucleus. The main clinical features of SCA subtypes are spinal cord, cerebellum, spinal nerve and cerebral nerve. A lesion of the sympathetic nerve, etc. A new pathogenic gene X was found in an autosomal recessive SCA family by sequencing the entire exon group. (because the article had not been published, the gene was temporarily replaced by X. The protein encoding the X gene is a newly discovered ubiquitin activator (E1), which activates the ubiquitin protein encoded by the M gene. The Ubiquitin binding enzyme (E _ 2) of M was found to be A, the ubiquitin ligase (E _ 3) was B and the known substrate of M was C _ (2). It was found that the ubiquitin modification system was involved in nematode reproduction, development and resistance to harmful environmental factors. The X gene knockout mouse embryos died in the related study of mouse model. Objective the function of the gene: X in organism and the pathogenesis of X-induced SCA need to be further studied. By studying the model of Drosophila, we found that X gene can simulate the occurrence of SCA disease well. Methods: the abnormal phenotype of Drosophila melanogaster was observed by knockdown, of X gene induced by UAS-GAL4 system and other important molecules in M class ubiquitin modification pathway. Results: the low expression of X gene induced by GAL4 expression in the whole body could induce the drosophila melanogaster to exhibit stable single-wing or double-wing vertical spread phenotype at 25 鈩，
本文编号：2225191
[Abstract]:Spinal cerebellar ataxia (SCA, spinocerebellar ataxia) is a kind of hereditary neurodegenerative disease. More than 30 SCA subtypes (DRPLA, SCA1-8,10-23,25-31) have been found. Due to abnormal amplification of CAG repeats in most SCA subtypes, polyglutamine chain mutated proteins form intranuclear inclusions in the nucleus. The main clinical features of SCA subtypes are spinal cord, cerebellum, spinal nerve and cerebral nerve. A lesion of the sympathetic nerve, etc. A new pathogenic gene X was found in an autosomal recessive SCA family by sequencing the entire exon group. (because the article had not been published, the gene was temporarily replaced by X. The protein encoding the X gene is a newly discovered ubiquitin activator (E1), which activates the ubiquitin protein encoded by the M gene. The Ubiquitin binding enzyme (E _ 2) of M was found to be A, the ubiquitin ligase (E _ 3) was B and the known substrate of M was C _ (2). It was found that the ubiquitin modification system was involved in nematode reproduction, development and resistance to harmful environmental factors. The X gene knockout mouse embryos died in the related study of mouse model. Objective the function of the gene: X in organism and the pathogenesis of X-induced SCA need to be further studied. By studying the model of Drosophila, we found that X gene can simulate the occurrence of SCA disease well. Methods: the abnormal phenotype of Drosophila melanogaster was observed by knockdown, of X gene induced by UAS-GAL4 system and other important molecules in M class ubiquitin modification pathway. Results: the low expression of X gene induced by GAL4 expression in the whole body could induce the drosophila melanogaster to exhibit stable single-wing or double-wing vertical spread phenotype at 25 鈩，
本文编号：2225191
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