线虫脊髓小脑性共济失调相关基因atx-3的功能研究

发布时间：2018-07-11 10:58

  本文选题：脊髓小脑性共济失调 + 线虫　； 参考：《中南大学》2014年硕士论文

【摘要】：背景：脊髓小脑性共济失调(Spinocerebellar ataxia, SCA)是一组具有高度临床和遗传异质性的常染色体显性遗传性神经系统退行性疾病。其临床症状以小脑性共济失调为主要特征。目前,已至少有20个SCAs的致病基因被定位克隆。但是这些致病基因在SCAs的发病机制中的具体作用仍不十分清楚。SCA3(亦称为Machado-Joseph病)是世界范围内最常见的SCA亚型,其发病主要是由于致病基因ataxin-3的C末端发生多聚谷氨酰胺数目的异常扩增引起。为了进一步了解ataxin-3的正常生理功能,我们对ataxin-3的线虫同源基因atx-3在寿命调节和应激抵抗中的作用进行了研究,并探索其与胰岛素-胰岛素样生长因子1信号通路(IIS)的关系。 方法：我们构建了chn-1(by155); atx-3(gk193)双突变线虫(chn-1为热休克蛋白同源蛋白70羧基端作用蛋白编码基因CHIP的线虫同源基因,CHIP突变可导致常染色体隐性遗传小脑性共济失调)；随后,分别检测了N2野生型,chn-1(by155),atx-3(gkl93) chn-1(by155);atx-3(gkl93)4种品系线虫在20℃和35℃热休克条件下的寿命和运动能力；同时我们利用上述4种品系线虫通过杂交获得包含daf-2(e1370)或daf-16(m26)的IIS相关杂交线虫,并分别检测了其在20℃和35℃热休克条件下的寿命和运动能力。 结果：我们发现N2,chn-1(by155), atx-3(gk193)chn-1(by155);atx-3(gk193)4种品系线虫在20℃的寿命和运动能力没有显著差异；在热休克情况下,chn-1突变线虫表现出寿命缩短和运动衰退的表型,而atx-3突变可以提高chn-1突变线虫的寿命和运动能力；在热休克情况下,daf-2突变明显提高atx-3突变、chn-1突变和atx-3、chn-1双突变线虫的寿命和运动能力,而daf-16突变可缩短及减弱atx-3突变和atx-3、chn-1双突变线虫的寿命和运动能力,但对chn-1单突变线虫的表型没有明显影响。 结论:chn-1突变导致线虫在热休克条件下的寿命缩短和运动衰退；atx-3突变可挽救chn-1突变线虫在热休克条件下的表型；chn-1和atx-3可能通过胰岛素-胰岛素样生长因子1信号通路影响线虫在热休克条件下的应激抵抗能力;ataxin-3和CHIP突变导致的共济失调可能和胰岛素-胰岛素样生长因子1信号通路的变化有关。
[Abstract]:Background: spinocerebellar ataxia (SCA) is a group of autosomal dominant neurodegenerative diseases with high clinical and genetic heterogeneity. Its clinical symptoms are mainly characterized by cerebellar ataxia. At present, at least 20 pathogenic genes of as have been located and cloned. But the role of these genes in the pathogenesis of scas remains unclear. SCA3 (also known as Machado-Joseph disease) is the most common SCA subtype worldwide. The pathogenesis was mainly caused by the abnormal amplification of polyglutamine at the C-terminal of the pathogenic gene ataxin-3. In order to further understand the normal physiological function of ataxin-3, we studied the role of atx-3, a nematode homologous gene of ataxin-3, in life regulation and stress resistance, and explored its relationship with insulin-like growth factor-1 signaling pathway. Methods: we constructed chn-1 (by155), atx-3 (gk193) double mutant nematode (Heat-shock protein homologous protein 70 carboxyl terminal protein gene Chip gene mutation), which can lead to autosomal recessive cerebellar ataxia. The life span and mobility of four nematode strains of N _ 2 wild type chn-1 (by155) atx-3 (gkl93) chn-1 (by155) anatx-3 (gkl93) under heat shock at 20 鈩，

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