Single-cell transcriptomics of mammalian prion diseases identifies dynamic gene signatures shared between species [human_bulkRNAseq]

Mammalian prion diseases are fatal and transmissible neurological conditions caused by the propagation of prions, self-replicating multimeric assemblies of misfolded forms of host cellular prion protein. Despite extensive studies investigating the changes in transcriptional profiles in prion diseases the mechanisms by which prion diseases induce cellular toxicity, including changes in gene expression profiles are yet to be fully characterized. Here, we took advantage of the recent developments in single-cell technologies and performed an unbiased whole-transcriptome single-nucleus transcriptomic analysis in prion disease. Overall design: We selected 10 individuals from archived tissue collected by the National Prion Clinic. For our control group, we included frontal cortex samples from individuals with low-level AD pathology or pathological ageing provided by the Queen Square Brain Bank. These samples (N = 10) were matched for sex (male = 4 sCJD and 5 controls; female = 6 sCJD and 5 controls) but not age (mean age for sCJD = 70.4 years, SD = 8.6; mean age for controls = 83.7 years, SD = 8.6). We were also able to source 3 non-dominant frontal lobe biopsy samples from sCJD patients. The control samples for this group included frontal lobe biopsies from non-neurodegenerative disease controls with mixed clinical diagnoses and only non-specific minor histological changes (pathological non-diagnostic samples), provided by BRAIN UK. These samples (N = 3) were sampled similarly to the biopsies and individuals were matched for sex (male = 2 sCJD and 2 controls; female = 1 sCJD and 1 control) while the age was matched only partially (mean age for sCJD = 56.6, SD = 13.3; mean age for controls = 60.6, SD = 3.3).

哺乳动物朊病毒病（prion diseases）是一类致命且可传播的神经系统疾病，由朊病毒（prions）的增殖所引发；朊病毒是宿主细胞朊蛋白（host cellular prion protein）错误折叠形成的自我复制多聚体组装体。尽管已有大量研究针对朊病毒病的转录谱（transcriptional profiles）变化展开探索，但该病诱导细胞毒性的机制（包括基因表达谱（gene expression profiles）改变）仍未得到完全阐明。本研究借助单细胞技术领域的新近进展，针对朊病毒病开展了无偏倚的全转录组单细胞核转录组分析（whole-transcriptome single-nucleus transcriptomic analysis）。

总体设计：我们从国家朊病毒诊所（National Prion Clinic）存档的组织样本中选取10名受试者。对照组纳入由女王广场脑库（Queen Square Brain Bank）提供的、伴有轻度阿尔茨海默病（Alzheimer's disease, AD）病理或病理性衰老的受试者的额叶皮层样本。该组样本（N=10）在性别上进行匹配：散发性克雅氏病（sporadic Creutzfeldt-Jakob disease, sCJD）组男性4例、对照组5例；散发性克雅氏病组女性6例、对照组5例，但年龄未匹配：散发性克雅氏病组平均年龄为70.4岁，标准差（standard deviation, SD）=8.6；对照组平均年龄为83.7岁，标准差=8.6。

我们还收集了3份来自散发性克雅氏病患者的非优势侧额叶活检样本。该组的对照样本为英国脑库（BRAIN UK）提供的、来自伴有混合临床诊断结果且仅存在非特异性轻微组织学改变（病理学非诊断性样本）的无神经退行性疾病病史受试者的额叶活检样本。该组样本（N=3）的采样方式与活检组一致，性别匹配：散发性克雅氏病组男性2例、对照组2例；散发性克雅氏病组女性1例、对照组1例，但年龄仅部分匹配：散发性克雅氏病组平均年龄为56.6岁，标准差=13.3；对照组平均年龄为60.6岁，标准差=3.3。