Frontotemporal dementia and amyotrophic lateral sclerosis are common forms of neurodegenerative disease which share overlapping genetics and pathologies. Crucially, no significantly disease-modifying treatments are available for either disease. Identifying the earliest changes which initiate neuronal dysfunction is important for designing effective intervention therapeutics. The genes mutated in genetic forms of frontotemporal dementia and amyotrophic lateral sclerosis have diverse cellular functions, and multiple disease mechanisms have been proposed for both. Identification of a convergent disease mechanism in frontotemporal dementia and amyotrophic lateral sclerosis would focus research for a targetable pathway which could potentially effectively treat all forms of frontotemporal dementia and amyotrophic lateral sclerosis (both familial and sporadic). Synaptopathies are diseases resulting from physiological dysfunction of synapses, and define the earliest stages in multiple neuronal diseases, with synapse loss a key feature in dementia. At the presynapse, the process of synaptic vesicle recruitment, fusion and recycling is necessary for activity-dependent neurotransmitter release. The unique distal location of the presynaptic terminal means the tight spatio-temporal control of presynaptic homeostasis is dependent on efficient local protein translation and degradation. Recently, numerous publications have shown that mutations associated with frontotemporal dementia and amyotrophic lateral sclerosis present with synaptopathy characterised by presynaptic dysfunction. This review will describe the complex local signalling and membrane trafficking events that occur at the presynapse to facilitate neurotransmission and will summarise recent publications linking frontotemporal dementia/amyotrophic lateral sclerosis genetic mutations to presynaptic function. This evidence indicates that presynaptic synaptopathy is an early and convergent event in frontotemporal dementia and amyotrophic lateral sclerosis and illustrates the need for further research in this area, to identify potential therapeutic targets with the ability to impact this convergent pathomechanism.

中文翻译：

---

突触病：额颞叶痴呆和肌萎缩侧索硬化症的突触前会聚

额颞叶痴呆和肌萎缩侧索硬化症是神经退行性疾病的常见形式，它们具有重叠的遗传学和病理学特征。至关重要的是，对于这两种疾病都没有明显的疾病缓解治疗方法。识别引发神经元功能障碍的最早变化对于设计有效的干预疗法非常重要。额颞叶痴呆和肌萎缩侧索硬化症的基因突变基因具有不同的细胞功能，并且已经提出了这两种疾病的多种疾病机制。确定额颞叶痴呆和肌萎缩侧索硬化症的聚合疾病机制将集中研究有针对性的途径，该途径可能有效治疗所有形式的额颞叶痴呆和肌萎缩侧索硬化症（家族性和散发性）。突触病是由突触生理功能障碍引起的疾病，定义了多种神经元疾病的最早阶段，其中突触丧失是痴呆症的一个关键特征。在突触前，突触小泡的招募、融合和再循环过程对于活动依赖性神经递质的释放是必要的。突触前末端独特的远端位置意味着突触前稳态的严格时空控制依赖于有效的局部蛋白质翻译和降解。最近，大量出版物表明，与额颞叶痴呆和肌萎缩侧索硬化症相关的突变会导致以突触前功能障碍为特征的突触病。这篇综述将描述发生在突触前以促进神经传递的复杂的局部信号传导和膜运输事件，并将总结最近发表的将额颞叶痴呆/肌萎缩侧索硬化症基因突变与突触前功能联系起来的出版物。这一证据表明，突触前突触病是额颞叶痴呆和肌萎缩侧索硬化症的早期聚合事件，并说明需要在该领域进行进一步研究，以确定能够影响这种聚合病理机制的潜在治疗靶点。