Nakano Yuta, Takahashi-Fujigasaki Junko, Sengoku Renpei, Kanemaru Kazutomi, Arai Tomio, Kanda Takashi, Murayama Shigeo
Brain Bank for Aging Research, Department of Neuropathology, Department of Neurology, and Department of Pathology; Tokyo Metropolitan Geriatric Hospital and Institution of Gerontology, Tokyo, Japan; Department of Neurology and Clinical Neuroscience; and Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
J Neuropathol Exp Neurol. 2017 Jul 1;76(7):585-594. doi: 10.1093/jnen/nlx039.
Neuronal intranuclear hyaline inclusion disease (NIHID) is a neurodegenerative disorder characterized by the presence of eosinophilic nuclear inclusions (NIs) in diverse cell lines in systemic organs. Adult-onset NIHID typically manifests with dementia associated with leukoencephalopathy. The detection of NIs in skin biopsies is useful for an antemortem diagnosis. A previous analysis suggested that NIs in NIHID originated from nuclear bodies (NBs), an important nuclear domain related to the ubiquitin-p62-mediated protein degradation system. In this study, we analyzed skin samples from 5 NIHID and 5 control cases immunohistochemically and electron microscopically. In the control cases, small but significant amounts of ubiquitin- and p62-positive intranuclear structures were found. These structures were consistently colocalized with promyelocytic leukemia protein (PML), an essential component of NBs, in particular when activated. The p62- and PML-positive structures were more frequently found in NIHID cases. Activated NBs, having a core and a shell, were observed by electron microscopy in control but not in NIHID cases. Instead, immature and mature filamentous NIs were found only in the NIHID cases. Our results indicate that NBs could not be normally activated in the NIHID, and an abnormal alteration of NBs might be related to the pathogenesis of NIHID.
神经元核内透明包涵体病（NIHID）是一种神经退行性疾病，其特征是全身器官的多种细胞系中存在嗜酸性核包涵体（NIs）。成人发病的NIHID通常表现为与白质脑病相关的痴呆。皮肤活检中NIs的检测有助于生前诊断。先前的分析表明，NIHID中的NIs起源于核小体（NBs），这是一个与泛素-p62介导的蛋白质降解系统相关的重要核结构域。在本研究中，我们对5例NIHID患者和5例对照患者的皮肤样本进行了免疫组织化学和电子显微镜分析。在对照病例中，发现了少量但显著的泛素和p62阳性核内结构。这些结构始终与核小体的重要组成部分早幼粒细胞白血病蛋白（PML）共定位，尤其是在激活时。p62和PML阳性结构在NIHID病例中更常见。通过电子显微镜在对照病例中观察到具有核心和外壳的激活核小体，但在NIHID病例中未观察到。相反，仅在NIHID病例中发现了不成熟和成熟的丝状NIs。我们的结果表明，NIHID中核小体不能正常激活，核小体的异常改变可能与NIHID的发病机制有关。
