Abnormal ubiquitination of axons in normally myelinated white matter in multiple sclerosis brain
Abnormal ubiquitination of axons in normally myelinated white matter in multiple sclerosis brain
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DOI：
10.1046/j.1365-2990.2002.00372.x
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发表时间：
2002-02-01
影响因子：
5
通讯作者：
Palmucci, L
中科院分区：
文献类型：
--
作者：
Giordana, MT;Richiardi, P;Palmucci, L
多发性硬化症（MS）病变的标志是轴突保留的炎性脱髓鞘。最近的神经病理学和神经放射学研究表明，在斑块和正常的白质中都发生了轴突的结构改变。更好地了解多发性硬化症的轴突损伤是很重要的，因为这可能是导致永久性残疾的原因。我们研究了6例MS患者（年龄39-66岁）大脑中泛素的免疫反应性，泛素是一种检测神经系统病理状态下轴突营养不良和异常蛋白积累的敏感方法。组织块用福尔马林固定，石蜡包埋。采用一组抗体：抗泛素、抗神经丝（SMI-31 + SMI-32）、抗淀粉样蛋白前体蛋白、抗pgp9.5。我们将注意力集中在慢性斑块上，通过巨噬细胞中缺乏Luxol Fast Blue b阳性包涵体来识别。SMI-31+SMI-32显示斑块内存在不同数量的轴突；斑块内的轴突网络比外部更松散。慢性斑块无泛素反应。在斑块周围正常髓鞘白质中，在斑块边缘附近和远处均可见致密颗粒状泛素免疫反应。在对照组大脑中没有发现类似的染色。泛素化是蛋白质非溶酶体降解途径的第一步。目前的研究结果表明，斑块外轴突的这种蛋白水解途径出现紊乱，可能是由于斑块内轴突段髓磷脂的慢性缺乏。多发性硬化症的轴突变化频谱似乎比预期的更宽，包括明显正常的白质。
The hallmark of the lesions in multiple sclerosis (MS) is inflammatory demyelination with sparing of axons. Recent neuropathological and neuroradiological investigations show that structural changes of the axons occur, both in plaques and in the normal appearing white matter. A better understanding of the axonal damage in MS is important, since this may be responsible for permanent disability. We have investigated the immunoreactivity for ubiquitin, a sensitive method to detect axonal dystrophy and accumulation of abnormal proteins in pathological conditions of the nervous system, in the brains of six cases of MS (age range 39-66 years). Tissue blocks were fixed in formalin and embedded in paraffin. A panel of antibodies was used: anti-ubiquitin, anti-neurofilament (SMI-31 + SMI-32), anti-amyloid precursor protein and anti-PGP9.5. We focused our attention on chronic plaques, recognized by the absence of Luxol Fast Blue B-positive inclusions in macrophages. SMI-31+SMI-32 showed the presence of a variable amount of axons within the plaques; the axonal network within the plaques was looser than outside. No ubiquitin reactivity was present in chronic plaques. In the normally myelinated white matter surrounding the plaques, a dense granular ubiquitin immunoreactivity was found both near and far from the plaque edge. No similar staining was found in control brains. Ubiquitination is the first step of a non-lysosomal degradation pathway of proteins. The present findings suggest a derangement of this proteolytic pathway in the axons outside the plaques, possibly as a consequence of chronic absence of myelin in the axonal segment inside the plaque. The spectrum of axonal changes in MS appears to be wider than expected and involves the apparently normal white matter.