突变泛素表达和蛋白稳态失调在纪伊 ALS/帕金森病痴呆复合征大脑中的作用。

Expression of Mutant Ubiquitin and Proteostasis Impairment in Kii Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex Brains.

机构信息

From the Departments of Translational Neuroscience and Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Department of Oncologic Pathology, Mie University, Graduate School of Medicine.

出版信息

J Neuropathol Exp Neurol. 2020 Aug 1;79(8):902-907. doi: 10.1093/jnen/nlaa056.

DOI:10.1093/jnen/nlaa056

PMID:32647880

Abstract

Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder that is endemic to the Kii peninsula of Japan. The disorder is clinically characterized by a variable combination of parkinsonism, dementia, and motor neuron symptoms. Despite extensive investigations, the etiology and pathogenesis of ALS/PDC remain unclear. At the neuropathological level, Kii ALS/PDC is characterized by neuronal loss and tau-dominant polyproteinopathy. Here, we report the accumulation of several proteins involved in protein homeostasis pathways, that is, the ubiquitin-proteasome system and the autophagy-lysosome pathway, in postmortem brain tissue from a number of Kii ALS/PDC cases (n = 4). Of particular interest is the presence of a mutant ubiquitin protein (UBB+1), which is indicative of disrupted ubiquitin homeostasis. The findings suggest that abnormal protein aggregation is linked to impaired protein homeostasis pathways in Kii ALS/PDC.

摘要

日本纪伊半岛特有的进行性神经退行性疾病——纪伊肌萎缩侧索硬化/帕金森病痴呆复合征（Kii ALS/PDC），其临床表现为帕金森病、痴呆和运动神经元症状的多变组合。尽管进行了广泛的研究，但 Kii ALS/PDC 的病因和发病机制仍不清楚。在神经病理学水平，Kii ALS/PDC 的特征是神经元丧失和以 tau 为主的多蛋白病。在这里，我们报道了在多个 Kii ALS/PDC 病例（n=4）的死后脑组织中积累了几种参与蛋白质稳态途径的蛋白质，即泛素-蛋白酶体系统和自噬-溶酶体途径。特别值得注意的是存在一种突变的泛素蛋白（UBB+1），这表明泛素稳态受到破坏。这些发现表明，异常蛋白聚集与 Kii ALS/PDC 中蛋白质稳态途径受损有关。