Godlewski Jakub, Lenart Jacek, Salinska Elzbieta
Affiliation Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Affiliation Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
Noncoding RNA. 2019 Feb 23;5(1):20. doi: 10.3390/ncrna5010020.
The mammalian brain is made up of billions of neurons and supporting cells (glial cells), intricately connected. Molecular perturbations often lead to neurodegeneration by progressive loss of structure and malfunction of neurons, including their death. On the other side, a combination of genetic and cellular factors in glial cells, and less frequently in neurons, drive oncogenic transformation. In both situations, microenvironmental niches influence the progression of diseases and therapeutic responses. Dynamic changes that occur in cellular transcriptomes during the progression of developmental lineages and pathogenesis are controlled through a variety of regulatory networks. These include epigenetic modifications, signaling pathways, and transcriptional and post-transcriptional mechanisms. One prominent component of the latter is small non-coding RNAs, including microRNAs, that control the vast majority of these networks including genes regulating neural stemness, differentiation, apoptosis, projection fates, migration and many others. These cellular processes are also profoundly dependent on the microenvironment, stemness niche, hypoxic microenvironment, and interactions with associated cells including endothelial and immune cells. Significantly, the brain of all other mammalian organs expresses the highest number of microRNAs, with an additional gain in expression in the early stage of neurodegeneration and loss in expression in oncogenesis. However, a mechanistic explanation of the concept of an apparent inverse correlation between the odds of cancer and neurodegenerative diseases is only weakly developed. In this review, we thus will discuss widespread de-regulation of microRNAome observed in these two major groups of brain pathologies. The deciphering of these intricacies is of importance, as therapeutic restoration of pre-pathological microRNA landscape in neurodegeneration must not lead to oncogenesis and vice versa. We thus focus on microRNAs engaged in cellular processes that are inversely regulated in these diseases. We also aim to define the difference in microRNA networks between pro-survival and pro-apoptotic signaling in the brain.
哺乳动物的大脑由数十亿个神经元和支持细胞（神经胶质细胞）组成，它们相互连接错综复杂。分子扰动常常通过神经元结构的逐渐丧失和功能异常（包括神经元死亡）导致神经退行性变。另一方面，神经胶质细胞中的遗传和细胞因素组合，以及较少情况下神经元中的这些因素，驱动致癌转化。在这两种情况下，微环境生态位都会影响疾病的进展和治疗反应。在发育谱系进展和发病机制过程中细胞转录组发生的动态变化是通过多种调控网络来控制的。这些调控网络包括表观遗传修饰、信号通路以及转录和转录后机制。后者的一个突出组成部分是小非编码RNA，包括微小RNA，它们控制着绝大多数这些网络，包括调节神经干性、分化、凋亡、投射命运、迁移等的基因。这些细胞过程也深深依赖于微环境、干性生态位、低氧微环境以及与包括内皮细胞和免疫细胞在内的相关细胞的相互作用。值得注意的是，在所有其他哺乳动物器官中，大脑表达的微小RNA数量最多，在神经退行性变早期表达增加，而在肿瘤发生时表达减少。然而，对于癌症和神经退行性疾病发生几率之间明显负相关这一概念的机制解释还很薄弱。因此，在本综述中，我们将讨论在这两大类脑部疾病中观察到的微小RNA组的广泛失调。破解这些错综复杂的关系很重要，因为在神经退行性变中治疗性恢复病理前的微小RNA格局不能导致肿瘤发生，反之亦然。因此，我们关注参与这些疾病中反向调控的细胞过程的微小RNA。我们还旨在定义大脑中促生存和促凋亡信号传导之间微小RNA网络的差异。
