Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3:: In vivo evidence
Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3:: In vivo evidence
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DOI：
10.1523/jneurosci.4540-06.2007
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发表时间：
2007-07-11
影响因子：
5.3
通讯作者：
Riess, Olaf
中科院分区：
文献类型：
--
作者：
Bichelmeier, Ulrike;Schmidt, Thorsten;Riess, Olaf
脊髓小脑型共济失调3型(SCA3)是一种常染色体显性遗传性神经退行性疾病，由MJD1基因CAG重复序列扩增导致ATAX3蛋白多聚谷氨酰胺重复序列扩增所致。为了研究疾病的进程，我们用分别包含15、70或148个CAG重复序列的全长ataxin-3构建了SCA3转基因小鼠。对照组小鼠(15只CAG)表型正常，没有神经病理学发现。然而，带有扩展多谷氨酰胺重复序列的ataxin-3转基因小鼠受到强烈的神经表型的严重影响，包括震颤、行为缺陷、运动和探索活动严重减少、驼背和3至6个月大时过早死亡。免疫组织化学染色的神经病理学检查显示，大量神经元内有泛素和ataxin-3阳性的包涵体。将含有148个CAG的ataxin-3导向细胞核，发现了一个更明显的表型，包涵体更多，死亡更早，而具有相同结构但附在核输出信号上的转基因小鼠出现了包裹体较少的较温和表型。这些研究表明，SCA3在体内的症状表现需要ataxin-3的核定位。
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited neurodegenerative disorder caused by the expansion of a CAG repeat in the MJD1 gene resulting in an expanded polyglutamine repeat in the ataxin-3 protein. To study the course of the disease, we generated transgenic mice for SCA3 using full-length ataxin-3 constructs containing 15, 70, or 148 CAG repeats, respectively. Control mice (15 CAGs) were phenotypically normal and had no neuropathological findings. However, mice transgenic for ataxin-3 with expanded polyglutamine repeats were severely affected by a strong neurological phenotype with tremor, behavioral deficits, strongly reduced motor and exploratory activity, a hunchback, and premature death at 3 to 6 months of age. Neuropathological examination by immunohistochemical staining revealed ubiquitin- and ataxin-3-positive intranuclear inclusion bodies in a multitude of neurons. Directing ataxin-3 with 148 CAGs to the nucleus revealed an even more pronounced phenotype with more inclusions and earlier death, whereas mice transgenic with the same construct but attached to a nuclear export signal developed a milder phenotype with less inclusions. These studies indicate that nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3 in vivo.