Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro
Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro
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DOI：
10.1016/s0361-9230(01)00600-1
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发表时间：
2001-10-01
影响因子：
3.8
通讯作者：
Jodice, C
中科院分区：
文献类型：
--
作者：
Calabresi, V;Guida, S;Jodice, C
I 型脊髓小脑共济失调是一种神经退行性疾病，由 ataxin-1 蛋白中不间断的谷氨酰胺重复序列扩张引起。蛋白质聚集和对 1C2 单克隆抗体的免疫反应性是扩增的 ataxin-1 以及其他多聚谷氨酰胺疾病的两个独特的特征。在随机人群中发现了极少数未受影响的老年受试者携带扩展的ataxin-1等位基因的病例。然而，在这些等位基因中，谷氨酰胺延伸被组氨酸中断。由于缺乏表型，这些等位基因应被视为“正常”。最重要的是，这些不寻常等位基因的出现提供了一个独特的机会来研究扩展的ataxin-1的哪些分子特性不与多谷氨酰胺发病机制相关。为了实现这一目标，我们在体外比较了 1C2 抗体的免疫反应性以及形成中断和不间断等位基因聚集体的能力。免疫印迹显示，扩增中断的 ataxin-1 对 1C2 具有与正常 ataxin-1 类似的亲和力。相反，过滤分析显示，扩增中断的ataxin-1的聚集率与扩增不间断的ataxin-1相似。这些观察结果表明对 1C2 的亲和力与 ataxin-1 的自聚集并不直接相关。此外，自聚集不会直接受到组氨酸中断的影响。总之，这些结果支持这样的假设：神经元变性的机制是由蛋白质错误折叠而不是蛋白质聚集触发的。 (C) 2001 爱思唯尔科学公司。
Spinocerebellar ataxia type I is a neurodegenerative disease caused by expansion of an uninterrupted glutamine repeat in ataxin-1 protein. Protein aggregation and immunoreactivity to 1C2 monoclonal antibody are two distinct pathognomonic features of expanded ataxin-1, as well as of other polyglutamine disorders. Rare cases of non-affected elderly subjects carrying expanded ataxin-1 alleles were found in random population. However, in these alleles the glutamine stretch was interrupted by histidines. Due to lack of phenotype, these alleles should be considered "normal". Most importantly, occurrence of these unusual alleles provides a unique opportunity to investigate which molecular properties of expanded ataxin-1 are not coupled to polyglutamine pathogenesis. Towards this goal, we compared in vitro the immunoreactivity to 1C2 antibody and the ability to form aggregates of interrupted and uninterrupted alleles. Immunoblotting showed that expanded-interrupted ataxin-1 had an affinity to 1C2 resembling that of normal ataxin-1. On the contrary, filter assay showed that aggregation rate of expanded-interrupted ataxin-1 resembles that of expanded-uninterrupted ataxin-1. These observations indicate that affinity for 1C2 does not directly correlate with self-aggregation of ataxin-1. Moreover, self-aggregation is not directly affected by histidine interruptions. In conclusion, these results support the hypothesis that mechanisms underlying neuronal degeneration are triggered by protein misfolding ather than by protein aggregation. (C) 2001 Elsevier Science Inc.