ATM immunolocalization in mouse neuronal endosomes: implications for ataxia-telangiectasia
ATM immunolocalization in mouse neuronal endosomes: implications for ataxia-telangiectasia
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DOI：
10.1016/s0006-8993(99)01813-2
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发表时间：
1999-09-25
期刊：
影响因子：
2.9
通讯作者：
Xu, Y
中科院分区：
文献类型：
--
作者：
Kuljis, RO;Chen, G;Xu, Y
共济失调-毛细血管扩张症（A-T）是一种具有多种表现的人类疾病，包括肿瘤、免疫功能障碍和神经变性。这种疾病是由于被称为ATM（A-T，突变）的基因突变引起的，这导致其蛋白质产物（小鼠中的Atm）缺乏，这是DNA损伤监测所必需的。Atm的这种核功能原则上解释了A-T中癌症和免疫缺陷的倾向，但不能解释导致最早临床表现和导致进行性残疾的神经变性。在这里，我们报告的超微结构证据的细胞质定位的ATM样免疫反应（ALI）内的内体在小鼠小脑皮质神经元，A-T的主要目标之一。用特异性识别Arm的两种单独的单克隆抗体获得ALI。相比之下，在野生型小鼠和Arm缺陷小鼠（“敲除”小鼠）中，可与ALI混淆的电子致密内体的数量可忽略不计。此外，有一个显着的优先分布的ATM免疫阳性内体的颗粒细胞层-在那里他们是存在于颗粒神经元-密度低得多的浦肯野和分子层。这些观察结果表明，内体结合的Atm可能对某些神经元的功能比其他神经元更重要-或者它在它们之间的处理方式不同-并且这种蛋白质可能参与细胞质中的分子分选。这与阐明Atm缺陷在A-T中神经变性的病理生物学中的作用有关。(C)1999年由Elsevier Science B. V.出版，版权所有。
Ataxia-telangiectasia (A-T) is a human disorder with pleiotropic manifestations that include neoplasms, immune dysfunction and neurodegeneration. The disorder is due to mutations in the gene known as ATM (A-T, mutated), which causes a deficiency in its protein product (Atm in mice) that is necessary for DNA damage surveillance. This nuclear function of Atm explains in principle the propensity to cancer and immunodeficiency in A-T, but not the neurodegeneration which results in the earliest clinical manifestations and causes progressive disability. Here we report ultrastructural evidence of cytoplasmic localization of Atm-like immunoreactivity (ALI) within endosomes in murine cerebellocortical neurons, one of the principal targets of A-T. The ALI was obtained with two separate monoclonal antibodies that recognize Arm specifically. By contrast, electron-dense endosomes that could be confused with ALI occur in negligible amounts in both wild-type mice and in mice deficient in Arm ("knockout" mice). Furthermore, there was a marked preferential distribution of Atm-immunopositive endosomes in the granule cell layer - where they are present in granule neurons - with a much lower density in the Purkinje and molecular layers. These observations suggest that endosome-bound Atm may be more important for the function of certain neurons than others - or that it is processed differently among them - and that this protein may be involved in molecular sorting in the cytoplasm. This is relevant to elucidating the role of Atm deficiency in the pathobiology of neurodegeneration in A-T. (C) 1999 Published by Elsevier Science B.V. All rights reserved.