Mofatteh Mohammad
Lincoln College, University of Oxford Oxford, UK.
Sir William Dunn School of Pathology, Medical Sciences Division, University of Oxford Oxford, UK.
Am J Neurodegener Dis. 2021 Feb 15;10(1):1-12. eCollection 2021.
The prevalence of neurodegenerative diseases is accelerating in rapidly aging global population. Novel and effective diagnostic and therapeutic methods are required to tackle the global issue of neurodegeneration in the future. A better understanding of the potential molecular mechanism causing neurodegeneration can shed light on dysfunctional processes in diseased neurons, which can pave the way to design and synthesize novel targets for early diagnosis during the asymptomatic phase of the disease. Abnormal protein aggregation is a hallmark of neurodegenerative diseases which can hamper transportation of cargoes into axons. Recent evidence suggests that disruption of local protein synthesis has been observed in neurodegenerative diseases. Because of their highly asymmetric structure, highly polarized neurons require trafficking of cargoes from the cell body to different subcellular regions to meet the extensive demands of cellular physiology. Localization of mRNAs and subsequent local translation to corresponding proteins in axons is a mechanism which allows neurons to rapidly respond to external stimuli as well as establishing neuronal networks by synthesizing proteins on demand. Axonal protein synthesis is required for axon guidance, synapse formation and plasticity, axon maintenance and regeneration in response to injury. Different types of excitatory and inhibitory neurons in the central and peripheral nervous systems have been shown to localize mRNA. Rising evidence suggests that the repertoire of localizing mRNA in axons can change during aging, indicating a connection between axonal mRNA trafficking and aging diseases such as neurodegeneration. Here, I briefly review the latest findings on the importance of mRNA localization and local translation in neurons and the consequences of their disruption in neurodegenerative diseases. In addition, I discuss recent evidence that dysregulation of mRNA localization and local protein translation can contribute to the formation of neurodegenerative diseases such as Alzheimer's disease, Amyotrophic Lateral Sclerosis, and Spinal Muscular Atrophy. In addition, I discuss recent findings on mRNAs localizing to mitochondria in neurodegeneration.
在全球人口快速老龄化的背景下，神经退行性疾病的患病率正在加速上升。未来需要新颖且有效的诊断和治疗方法来应对全球神经退行性变问题。更好地理解导致神经退行性变的潜在分子机制，有助于揭示患病神经元中的功能失调过程，这可为在疾病无症状阶段设计和合成早期诊断的新靶点铺平道路。异常蛋白质聚集是神经退行性疾病的一个标志，它会阻碍货物向轴突的运输。最近的证据表明，在神经退行性疾病中已观察到局部蛋白质合成的破坏。由于其高度不对称的结构，高度极化的神经元需要将货物从细胞体运输到不同的亚细胞区域，以满足细胞生理的广泛需求。轴突中mRNA的定位以及随后将其翻译为相应蛋白质，是一种使神经元能够快速响应外部刺激并通过按需合成蛋白质来建立神经网络的机制。轴突蛋白质合成对于轴突导向、突触形成和可塑性、轴突维持以及损伤后的再生是必需的。中枢和外周神经系统中不同类型的兴奋性和抑制性神经元已被证明可定位mRNA。越来越多的证据表明，轴突中定位mRNA的种类在衰老过程中会发生变化，这表明轴突mRNA运输与诸如神经退行性变等衰老疾病之间存在联系。在此，我简要回顾关于mRNA定位和局部翻译在神经元中的重要性及其在神经退行性疾病中破坏的后果的最新发现。此外，我讨论最近的证据，即mRNA定位和局部蛋白质翻译的失调可能导致诸如阿尔茨海默病、肌萎缩侧索硬化症和脊髓性肌萎缩症等神经退行性疾病的形成。此外，我还讨论了关于神经退行性变中线粒体定位的mRNA的最新发现。
