Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients
Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients
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DOI：
10.1093/brain/awh381
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发表时间：
2005-03-01
期刊：
影响因子：
14.5
通讯作者：
Sobue, G
中科院分区：
文献类型：
--
作者：
Adachi, H;Katsuno, M;Sobue, G
脊髓延髓肌萎缩症（SBMA）是一种遗传性成人发病的运动神经元疾病，由雄激素受体（AR）内的多聚谷氨酰胺（polyQ）束扩张引起，仅影响男性。特征性病理学发现是在残余运动神经元和某些内脏器官中由具有扩增的polyQ的突变体AR组成的核包涵体（NI）。我们在尸检时用1C 2（一种特异性识别扩增polyQ的抗体）对11名SBMA患者进行了免疫化学检查。我们的研究表明，突变体AR的弥漫性核积聚比分布在广泛的CNS核中的NI更频繁和更广泛，并且比迄今为止认为的更多的内脏器官。突变体AR积累也存在于细胞质中，特别是在高尔基体中;积累的细胞核或细胞质优势是组织特异性的。此外，在运动和感觉神经元的脊髓中的突变AR的弥漫性核积聚的程度与CAG重复序列的长度密切相关。因此，突变体AR的弥漫性核蓄积显然是神经学表现的基础上的一个主要发病过程，如在SBMA转基因小鼠中，而细胞质蓄积也可能有助于SBMA病理生理学。
Spinal and bulbar muscular atrophy (SBMA) is an inherited adult onset motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor (AR), affecting only males. The characteristic pathological finding is nuclear inclusions (NIs) consisting of mutant AR with an expanded polyQ in residual motor neurons, and in certain visceral organs. We immunohistochemically examined 11 SBMA patients at autopsy with 1C2, an antibody that specifically recognizes expanded polyQ. Our study demonstrated that diffuse nuclear accumulation of mutant AR was far more frequent and extensive than NIs being distributed in a wide array of CNS nuclei, and in more visceral organs than thus far believed. Mutant AR accumulation was also present in the cytoplasm, particularly in the Golgi apparatus; nuclear or cytoplasmic predominance of accumulation was tissue specific. Furthermore, the extent of diffuse nuclear accumulation of mutant AR in motor and sensory neurons of the spinal cord was closely related to CAG repeat length. Thus, diffuse nuclear accumulation of mutant AR apparently is a cardinal pathogenetic process underlying neurological manifestations, as in SBMA transgenic mice, while cytoplasmic accumulation may also contribute to SBMA pathophysiology.