Senataxin, the yeast Sen1p orthologue: Characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease
Senataxin, the yeast Sen1p orthologue: Characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease
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DOI：
10.1016/j.nbd.2006.02.007
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发表时间：
2006-07-01
影响因子：
6.1
通讯作者：
Bennett, Craig L.
中科院分区：
文献类型：
--
作者：
Chen, Ying-Zhang;Hashemi, Sayed H.;Bennett, Craig L.
严重的隐性小脑共济失调、共济失调-动眼神经失用 2 (AOA2) 和青少年发病的显性肌萎缩侧索硬化症 (ALS4) 是由 Senataxin (SETX) 基因突变引起的。为了开始表征这种疾病蛋白，我们开发了一种针对 SETX 的 DNA/RNA 解旋酶结构域的特异性抗体。在小鼠大脑中，SETX 集中在几个区域，包括小脑、海马和嗅球，具有一般神经元表达谱，与 NeuN 共定位。在培养的细胞中，我们发现 SETX 在细胞质中扩散，但在细胞核中，SETX 呈点状，与核仁标记物纤维蛋白共定位。在分化的非循环细胞中，核 SETX 不限于核仁，而是扩散在核质内，表明细胞周期依赖性定位。 SETX 错义突变聚集在 N 末端和解旋酶结构域内。 N 末端的标记导致蛋白质错位到核质并且无法输出到细胞质，这表明 N 末端可能对于正确的 SETX 定位至关重要。我们在此报告了 SETX 蛋白的首次表征，这可能为未来提供导致神经元死亡的新机制的见解。 (c) 2006 Elsevier Inc. 保留所有权利。
A severe recessive cerebellar ataxia, Ataxia-Oculomotor Apraxia 2 (AOA2) and a juvenile onset form of dominant amyotrophic lateral sclerosis (ALS4) result from mutations of the Senataxin (SETX) gene. To begin characterization this disease protein, we developed a specific antibody to the DNA/RNA helicase domain of SETX. In murine brain, SETX concentrates in several regions, including cerebellum, hippocampus and olfactory bulb with a general neuronal expression profile, colocalizing with NeuN. In cultured cells, we found that SETX was cytoplasmically diffuse, but in the nucleus, SETX was punctate, colocalizing with fibrillarin, a marker of the nucleolus. In differentiated non-cycling cells, nuclear SETX was not restricted to the nucleolus but was diffuse within the nucleoplasm, suggesting cell-cycle-dependent localization. SETX missense mutations cluster within the N-terminus and helicase domains. Flag tagging at the N-terminus caused protein mislocation to the nucleoplasm and failure to export to the cytoplasm, suggesting that the N-terminus may be essential for correct SETX localization. We report here the first characterization of SETX protein, which may provide future insights into a new mechanism leading to neuron death. (c) 2006 Elsevier Inc. All rights reserved.