Cellular Neurobiology, Institute for Developmental Biology and Neurobiology, Johannes Gutenberg-University of Mainz, Anselm-Franz-von-Bentzelweg 3, 55128, Mainz, Germany.
Neurochem Res. 2020 Mar;45(3):566-579. doi: 10.1007/s11064-019-02763-y. Epub 2019 Mar 6.
The formation of myelin around axons by oligodendrocytes (OL) poses an enormous synthetic and energy challenge for the glial cell. Local translation of transcripts, including the mRNA for the essential myelin protein Myelin Basic Protein (MBP) at the site of myelin deposition has been recognised as an efficient mechanism to assure proper myelin sheath assembly. Oligodendroglial precursor cells (OPCs) form synapses with neurons and may localise many additional mRNAs in a similar fashion to synapses between neurons. In some diseases in which demyelination occurs, an abundance of OPCs is present but there is a failure to efficiently remyelinate and to synthesise MBP. This compromises axonal survival and function. OPCs are especially sensitive to cellular stress as occurring in neurodegenerative diseases, which can impinge on their ability to translate mRNAs into protein. Stress causes the build up of cytoplasmic stress granules (SG) in which many RNAs are sequestered and translationally stalled until the stress ceases. Chronic stress in particular could convert this initially protective reaction of the cell into damage, as persistence of SG may lead to pathological aggregate formation or long-term translation block of SG-associated RNAs. The recent recognition that many neurodegenerative diseases often exhibit an early white matter pathology with a proliferation of surviving OPCs, renders a study of the stress-associated processes in oligodendrocytes and OPCs especially relevant. Here, we discuss a potential dysfunction of RNA regulation in myelin diseases such as Multiple Sclerosis (MS) and Vanishing white matter disease (VWM) and potential contributions of OL dysfunction to neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Fragile X syndrome (FXS).
少突胶质细胞（OL）在轴突周围形成髓鞘，这对神经胶质细胞来说是一个巨大的合成和能量挑战。在髓鞘沉积部位，包括髓鞘基本蛋白（MBP）的必需髓鞘蛋白的 mRNA 的局部翻译，已被认为是确保适当髓鞘组装的有效机制。少突胶质前体细胞（OPC）与神经元形成突触，并且可以以类似于神经元之间的突触的方式将许多其他 mRNA 定位在类似的方式中。在发生脱髓鞘的某些疾病中，存在大量的 OPC，但未能有效地进行髓鞘再生和合成 MBP。这会损害轴突的存活和功能。OPC 对神经退行性疾病中发生的细胞应激特别敏感，这会影响它们将 mRNA 翻译成蛋白质的能力。应激导致细胞质应激颗粒（SG）的积累，其中许多 RNA 被隔离并翻译停滞，直到应激停止。特别是慢性应激可能会将细胞的这种最初保护反应转化为损伤，因为 SG 的持续存在可能导致病理性聚集体形成或 SG 相关 RNA 的长期翻译阻断。最近的认识是，许多神经退行性疾病通常表现出早期的白质病理学，伴有存活的 OPC 增殖，这使得对少突胶质细胞和 OPC 中与应激相关的过程的研究变得特别相关。在这里，我们讨论了 RNA 调节在多发性硬化症（MS）和消失性白质病（VWM）等髓鞘疾病中的潜在功能障碍，以及 OL 功能障碍对肌萎缩侧索硬化症（ALS）、阿尔茨海默病（AD）和脆性 X 综合征（FXS）等神经退行性疾病的潜在贡献。
