Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human
Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human
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DOI：
10.1038/79162
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发表时间：
2000-09-01
期刊：
影响因子：
30.8
通讯作者：
Pulst, SM
中科院分区：
文献类型：
--
作者：
Huynh, DP;Figueroa, K;Pulst, SM
CAG DNA三核苷酸重复序列的不稳定性是导致多聚谷氨酰胺（polyQ）道扩展的几种神经退行性疾病的突变机制。具有长polyQ束的蛋白质具有增加的聚集趋势，通常作为截短片段形成泛素化的核内包涵体。我们使用培养的细胞、人脑和转基因小鼠系研究了是否有相似的特征定义了脊髓小脑共济失调2型（SCA 2）的发病机制。在SCA 2脑中，我们发现了细胞质而不是细胞核的微聚集体。用Q58表达共济失调蛋白-2的小鼠表现出进行性功能缺陷，伴随着浦肯野细胞树突状细胞的损失，最后是浦肯野细胞的损失。尽管在共济失调蛋白-1 [Q80]转基因系中观察到类似的功能缺陷和解剖学变化，但共济失调蛋白-2 [Q58]仍保持在细胞质中，没有可检测到的泛素化。
Instability of CAG DNA trinucleotide repeats is the mutational mechanism for several neurodegenerative diseases resulting in the expansion of a polyglutamine (polyQ) tract. Proteins with long polyQ tracts have an increased tendency to aggregate, often as truncated fragments forming ubiquitinated intranuclear inclusion bodies. We examined whether similar features define spinocerebellar ataxia type 2 (SCA2) pathogenesis using cultured cells, human brains and transgenic mouse lines. In SCA2 brains, we found cytoplasmic, but not nuclear, microaggregates. Mice expressing ataxin-2 with Q58 showed progressive functional deficits accompanied by loss of the Purkinje cell dendritic arbor and finally loss of Purkinje cells. Despite similar functional deficits and anatomical changes observed in ataxin-1[Q80] transgenic lines, ataxin-2[Q58] remained cytoplasmic without detectable ubiquitination.