Optineurin pathology in the spinal cord of amyotrophic lateral sclerosis/parkinsonism-dementia complex patients in Kii Peninsula, Japan
Optineurin pathology in the spinal cord of amyotrophic lateral sclerosis/parkinsonism-dementia complex patients in Kii Peninsula, Japan
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日本纪伊半岛肌萎缩侧索硬化症/帕金森病-痴呆症患者脊髓中的 Optineurin 病理学
DOI：
10.1111/bpa.12558
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发表时间：
2018
期刊：
影响因子：
6.4
通讯作者：
Murayama Shigeo
中科院分区：
文献类型：
--
作者：
Morimoto Satoru;Hatsuta Hiroyuki;Motoyama Rie;Kokubo Yasumasa;Ishiura Hiroyuki;Tsuji Shoji;Kuzuhara Shigeki;Murayama Shigeo
肌萎缩侧索硬化/帕金森痴呆综合征（ALS/PDC）是关岛和日本纪伊半岛（纪伊ALS/PDC）报道的一种地方性神经退行性疾病（1，4）。Kii ALS/PDC的临床特征包括帕金森综合征、痴呆、肌无力、肌萎缩、反射亢进和痉挛的独特组合，作为上下运动神经元损伤的症状。ALS/PDC中的神经病理学发现显示与大脑皮层和脑干中的神经细胞损失相关的许多神经纤维缠结（NFT）（6）。这些是ALS的典型病理学发现之外的，其包括反式反应DNA结合蛋白（TDP，TARDBP）-43病理学（3）。视神经磷酸酶基因（OPTN）已被鉴定为正常眼压性青光眼和原发性开角型青光眼的致病基因。视神经磷酸酶（OPTN）是一种与多种蛋白质相互作用的衔接蛋白。它参与调节许多细胞功能，包括从高尔基体到质膜的囊泡运输、内吞运输和导致NF-κ B活化的信号传导（10）。在家族性ALS患者中报告了OPTN的外显子5缺失、p.Q398 * 无义突变和p.E478G错义突变（5）。各种胞浆内包涵体，如绞样，嗜酸性圆形透明，和大的球形与中央透明核心，已被鉴定为使用抗OPTN抗体在脊髓前角细胞（AHC）的ALS与OPTN突变。这些也见于由超氧化物歧化酶1（SOD 1）突变引起的散发性ALS和家族性ALS（FALS）中。值得注意的是，OPTN阳性胞质内结构与抗泛素和抗TDP-43反应性共定位，表明OPTN可能与散发性ALS（SALS）、具有SOD 1突变的家族性FALS和具有OPTN突变的FALS中的常见病理机制相关（5）。在这里，我们通过胆碱乙酰转移酶（ChAT）染色测量了7名Kii ALS/PDC患者和8名年龄匹配的对照组脊髓中AHC的数量和大小。男性5例，平均年龄6 SD，5 73 6 9.0岁;三名女性，平均年龄5 - 67 ± 2.7岁，从东京都立老年病医院和老年病研究所招募）并检查OPTN，10例Kii ALS/PDC患者（平均6SD，年龄69 ± 5.1岁）脊髓中磷酸化TDP-43（pTDP-43）的免疫反应性。我们对6例Kii ALS/PDC患者进行了OPTN突变分析，以揭示OPTN是否与Kii ALS/PDC的病理机制相关。从参与本研究的所有患者家属处获得知情同意书。这项研究得到了
Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is an endemic neurodegenerative disease reported on Guam and the Kii Peninsula of Japan (Kii ALS/PDC)(1, 4). The clinical features of Kii ALS/PDC include unique combinations of parkinsonism, dementia, muscular weakness, amyotrophy, hyperreflexia and spasticity as symptoms of damage to the upper and lower motor neurons. Neuropathological findings in ALS/PDC show numerous neurofibrillary tangles (NFTs) associated with nerve cell loss in the cerebral cortex and brainstem (6). These are in addition to the typical pathological findings of ALS, which includes transactive response DNA-binding protein (TDP, TARDBP)-43 pathology (3).The optineurin gene (OPTN) has been identified as a causative gene for normal-tension glaucoma and primary open-angle glaucoma. Optineurin (OPTN) is an adaptor protein that interacts with various proteins. It is involved in regulating many cellular functions that include vesicular trafficking from the Golgi to plasma membrane, endocytic trafficking and signaling leading to NF-kB activation (10). The exon 5 deletion, p. Q398* nonsense and p. E478G missense mutations of OPTN have been reported in patients with familial ALS (5). Various intracytoplasmic inclusions, such as skein-like, eosinophilic round hyaline, and large spherical with central hyaline core, have been immunohistochemically identified using anti-OPTN antibodies in spinal cord anterior horn cells (AHCs) of ALS with OPTN mutations. These are also found in sporadic ALS and familial ALS (FALS) caused by superoxide dismutase 1 (SOD1) mutations. Remarkably, OPTN-positive intracytoplasmic structures co-localize with anti-ubiquitin and anti-TDP-43 reactivity, suggesting that OPTN might be associated with common pathomechanisms in sporadic ALS (SALS), familial FALS with SOD1 mutations, and FALS with OPTN mutations (5). Here, we measured the number and size of AHCs by choline acetyltransferase (ChAT) staining in the spinal cords of seven patients with Kii ALS/PDC and eight age-matched controls (five males, mean 6 SD age 5 73 6 9.0 years; three females, mean age 5 67 6 2.7 years, recruited from the Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology) and examined OPTN, and phosphorylated TDP-43 (pTDP-43) immunoreactivity in the spinal cords of 10 patients with Kii ALS/PDC (mean 6 SD, age 69 6 5.1 years). We performed mutational analysis of OPTN in six patients with Kii ALS/PDC to reveal whether OPTN is associated with the pathomechanisms of Kii ALS/PDC. Informed consent was obtained from the families of all patients who participated in this study. This study was approved by the