Mori Fumiaki, Tanji Kunikazu, Miki Yasuo, Toyoshima Yasuko, Sasaki Hidenao, Yoshida Mari, Kakita Akiyoshi, Takahashi Hitoshi, Wakabayashi Koichi
Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Neurosci Lett. 2018 Jan 1;662:389-394. doi: 10.1016/j.neulet.2017.10.061. Epub 2017 Oct 31.
mRNA turnover controls gene expression under various conditions in aging and neurodegenerative diseases. Polyglutamine (polyQ) diseases and intranuclear inclusion body disease (INIBD) are neurodegenerative diseases characterized by the formation of nuclear inclusions. These inclusions are immunopositive for several proteins associated with amyotrophic lateral sclerosis. In amyotrophic lateral sclerosis, the processing of RNA from gene transcription through degradation (RNA metabolism) has been reported to be altered. We hypothesized that the proteins associated with RNA metabolism are also involved in the formation of nuclear inclusions in polyQ diseases and INIBD. 3'-5' exoribonuclease DIS3L2 and 5'-3' exoribonuclease XRN1 play critical roles in mRNA decay. Using immunohistochemistry with antibodies against DIS3L2 and XRN1, we examined the brains of patients with polyQ diseases and INIBD and normal control subjects. In controls, immunoreactivity for DIS3L2 and XRN1 was found in the neuronal cytoplasm and neuropil, respectively. In INIBD, immunoreactivity for DIS3L2 and XRN1 was present in neuronal and glial nuclear inclusions. Co-localization of ubiquitin and DIS3L2 or XRN1 was demonstrated in these inclusions. In polyQ diseases, however, nuclear inclusions were immunonegative for DIS3L2 and XRN1. These findings suggest that sequestration of exoribonucleases to nuclear inclusions may be related to the pathogenesis of INIBD.
mRNA 周转在衰老和神经退行性疾病的各种条件下控制基因表达。多聚谷氨酰胺（polyQ）疾病和核内包涵体病（INIBD）是神经退行性疾病，其特征是形成核内包涵体。这些包涵体对几种与肌萎缩侧索硬化相关的蛋白质呈免疫阳性。在肌萎缩侧索硬化中，已报道从基因转录到降解的 RNA 加工过程（RNA 代谢）发生改变。我们假设与 RNA 代谢相关的蛋白质也参与 polyQ 疾病和 INIBD 中核内包涵体的形成。3'-5' 外切核糖核酸酶 DIS3L2 和 5'-3' 外切核糖核酸酶 XRN1 在 mRNA 衰变中起关键作用。使用针对 DIS3L2 和 XRN1 的抗体进行免疫组织化学，我们检查了 polyQ 疾病和 INIBD 患者以及正常对照受试者的大脑。在对照组中，分别在神经元细胞质和神经毡中发现了 DIS3L2 和 XRN1 的免疫反应性。在 INIBD 中，DIS3L2 和 XRN1 的免疫反应性存在于神经元和胶质细胞核内包涵体中。在这些包涵体中证实了泛素与 DIS3L2 或 XRN1 的共定位。然而，在 polyQ 疾病中，核内包涵体对 DIS3L2 和 XRN1 呈免疫阴性。这些发现表明外切核糖核酸酶被隔离到核内包涵体可能与 INIBD 的发病机制有关。
