Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.
Neuropathol Appl Neurobiol. 2013 Jun;39(4):320-34. doi: 10.1111/nan.12014.
Recent developments in our understanding of events underlying neurodegeneration across the central and peripheral nervous systems have highlighted the critical role that synapses play in the initiation and progression of neuronal loss. With the development of increasingly accurate and versatile animal models of neurodegenerative disease it has become apparent that disruption of synaptic form and function occurs comparatively early, preceding the onset of degenerative changes in the neuronal cell body. Yet, despite our increasing awareness of the importance of synapses in neurodegeneration, the mechanisms governing the particular susceptibility of distal neuronal processes are only now becoming clear. In this review we bring together recent developments in our understanding of cellular and molecular mechanisms regulating synaptic vulnerability. We have placed a particular focus on three major areas of research that have gained significant interest over the last few years: (i) the contribution of synaptic mitochondria to neurodegeneration; (ii) the contribution of pathways that modulate synaptic function; and (iii) regulation of synaptic degeneration by local posttranslational modifications such as ubiquitination. We suggest that targeting these organelles and pathways may be a productive way to develop synaptoprotective strategies applicable to a range of neurodegenerative conditions.
我们对中枢和周围神经系统神经退行性变相关事件的理解的最新进展强调了突触在神经元丧失的起始和进展中的关键作用。随着越来越精确和多功能的神经退行性疾病动物模型的发展，人们明显发现突触的形态和功能的破坏发生得相对较早，早于神经元胞体发生退行性变化之前。然而，尽管我们越来越意识到突触在神经退行性变中的重要性，但控制远端神经元过程的特定易感性的机制直到现在才变得清晰。在这篇综述中，我们汇集了我们对调节突触易损性的细胞和分子机制的理解的最新进展。我们特别关注了过去几年中引起广泛关注的三个主要研究领域：（i）突触线粒体对神经退行性变的贡献；（ii）调节突触功能的途径的贡献；和（iii）局部翻译后修饰（如泛素化）对突触退化的调节。我们认为，针对这些细胞器和途径可能是开发适用于多种神经退行性疾病的突触保护策略的有效方法。
