Neurodegenerative Diseases Research Group, Department of Pharmacy, School of Health Sciences, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece.
Network Center for Biomedical Research of Neurodegenerative Diseases, Institute Carlos III, Ministry of Health, 0890X L'Hospitalet de Llobregat, Spain.
Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19727-19735. doi: 10.1073/pnas.1803521116. Epub 2019 Sep 6.
Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein into an infectious cellular pathogen. Clinically characterized by rapidly progressive dementia and accounting for 85% of human prion disease cases, sporadic Creutzfeldt-Jakob disease (sCJD) is the prevalent human prion disease. Although sCJD neuropathological hallmarks are well-known, associated molecular alterations are elusive due to rapid progression and absence of preclinical stages. To investigate transcriptome alterations during disease progression, we utilized tg340-129MM mice infected with postmortem material from sCJD patients of the most susceptible genotype (MM1 subtype), a sCJD model that faithfully recapitulates the molecular and pathological alterations of the human disease. Here we report that transcriptomic analyses from brain cortex in the context of disease progression, reveal epitranscriptomic alterations (specifically altered RNA edited pathway profiles, eg., ER stress, lysosome) that are characteristic and possibly protective mainly for preclinical and clinical disease stages. Our results implicate regulatory epitranscriptomic mechanisms in prion disease neuropathogenesis, whereby RNA-editing targets in a humanized sCJD mouse model were confirmed in pathological human autopsy material.
朊病毒病是由正常朊病毒蛋白错误折叠成传染性细胞病原体引起的致命神经退行性疾病。散发性克雅氏病（sCJD）是最常见的人类朊病毒病，其临床特征为迅速进展性痴呆，占人类朊病毒病病例的 85%。尽管 sCJD 的神经病理学特征众所周知，但由于疾病进展迅速且缺乏临床前阶段，相关的分子改变仍难以捉摸。为了研究疾病进展过程中的转录组改变，我们利用感染了最易感染基因型（MM1 亚型）sCJD 患者死后组织的 tg340-129MM 小鼠作为 sCJD 模型，该模型忠实地再现了人类疾病的分子和病理改变。在这里，我们报告说，对疾病进展过程中大脑皮层的转录组分析显示，转录后修饰（特别是改变的 RNA 编辑途径谱，例如内质网应激、溶酶体）发生改变，这些改变主要在临床前和临床疾病阶段具有特征性和可能的保护作用。我们的结果表明，在朊病毒病神经发病机制中存在调节性转录后修饰机制，在人类 sCJD 小鼠模型中，RNA 编辑靶标在病理性人类尸检材料中得到了证实。
