IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, 40139, Bologna, Italy.
Department of Biomedical and NeuroMotor Sciences, DIBINEM, University of Bologna, 40123, Bologna, Italy.
Mol Neurobiol. 2019 Jul;56(7):5009-5024. doi: 10.1007/s12035-018-1421-1. Epub 2018 Nov 16.
Functional genomics applied to the study of RNA expression profiles identified several abnormal molecular processes in experimental prion disease. However, only a few similar studies have been carried out to date in a naturally occurring human prion disease. To better characterize the transcriptional cascades associated with sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, we investigated the global gene expression profile in samples from the frontal cortex of 10 patients with sCJD and 10 non-neurological controls by microarray analysis. The comparison identified 333 highly differentially expressed genes (hDEGs) in sCJD. Functional enrichment Gene Ontology analysis revealed that hDEGs were mainly associated with synaptic transmission, including GABA (q value = 0.049) and glutamate (q value = 0.005) signaling, and the immune/inflammatory response. Furthermore, the analysis of cellular components performed on hDEGs showed a compromised regulation of vesicle-mediated transport with mainly up-regulated genes related to the endosome (q value = 0.01), lysosome (q value = 0.04), and extracellular exosome (q value < 0.01). A targeted analysis of the retromer core component VPS35 (vacuolar protein sorting-associated protein 35) showed a down-regulation of gene expression (p value= 0.006) and reduced brain protein levels (p value= 0.002). Taken together, these results confirm and expand previous microarray expression profile data in sCJD. Most significantly, they also demonstrate the involvement of the endosomal-lysosomal system. Since the latter is a common pathogenic pathway linking together diseases, such as Alzheimer's and Parkinson's, it might be the focus of future studies aimed to identify new therapeutic targets in neurodegenerative diseases.
应用功能基因组学研究 RNA 表达谱，在实验性朊病毒病中鉴定出几种异常的分子过程。然而，迄今为止，在自然发生的人类朊病毒病中，只有少数类似的研究。为了更好地描述与散发性克雅氏病（sCJD）相关的转录级联，我们通过微阵列分析研究了来自 10 例 sCJD 患者和 10 例非神经对照组额皮质样本的全基因表达谱。比较鉴定出 sCJD 中 333 个高度差异表达基因（hDEGs）。功能富集基因本体论分析表明，hDEGs 主要与突触传递有关，包括 GABA（q 值=0.049）和谷氨酸（q 值=0.005）信号转导和免疫/炎症反应。此外，对 hDEGs 进行的细胞成分分析表明，囊泡介导的运输受到干扰，主要上调与内体（q 值=0.01）、溶酶体（q 值=0.04）和细胞外外泌体（q 值<0.01）相关的基因。对逆行核心成分 VPS35（空泡蛋白分选相关蛋白 35）的靶向分析显示基因表达下调（p 值=0.006）和脑蛋白水平降低（p 值=0.002）。总之，这些结果证实并扩展了 sCJD 中以前的微阵列表达谱数据。最重要的是，它们还证明了内体-溶酶体系统的参与。由于后者是将阿尔茨海默病和帕金森病等疾病联系在一起的常见致病途径，因此它可能是未来旨在确定神经退行性疾病新治疗靶点的研究的重点。
