Centre for Clinical Brain Science, Edinburgh University, Edinburgh, UK.
Hum Mol Genet. 2019 Nov 21;28(R2):R219-R225. doi: 10.1093/hmg/ddz178.
Over 130 brain diseases are caused by mutations that disrupt genes encoding the proteome of excitatory synapses. These include neurological and psychiatric disorders with early and late onset such as autism, schizophrenia and depression and many other rarer conditions. The proteome of synapses is highly complex with over 1000 conserved proteins which are differentially expressed generating a vast, potentially unlimited, number of synapse types. The diversity of synapses and their location in the brain are described by the synaptome. A recent study has mapped the synaptome across the mouse brain, revealing that synapse diversity is distributed into an anatomical architecture observed at scales from individual dendrites to the whole systems level. The synaptome architecture is built from the hierarchical expression and assembly of proteins into complexes and supercomplexes which are distributed into different synapses. Mutations in synapse proteins change the synaptome architecture leading to behavioral phenotypes. Mutations in the mechanisms regulating the hierarchical assembly of the synaptome, including transcription and proteostasis, may also change synapse diversity and synaptome architecture. The logic of synaptome hierarchical assembly provides a mechanistic framework that explains how diverse genetic disorders can converge on synapses in different brain circuits to produce behavioral phenotypes.
超过 130 种脑部疾病是由突变引起的，这些突变会破坏编码兴奋性突触蛋白组的基因。这些疾病包括神经和精神障碍，包括自闭症、精神分裂症和抑郁症等早期和晚期发病的疾病，以及许多其他更为罕见的疾病。突触的蛋白组非常复杂，有超过 1000 种保守蛋白，这些蛋白的差异表达产生了大量、潜在无限的突触类型。突触的多样性及其在大脑中的位置由突触组描述。最近的一项研究在整个小鼠大脑中绘制了突触组图谱，揭示了突触多样性分布在从单个树突到整个系统水平的解剖结构中。突触组的结构是由蛋白质的层次表达和组装成复合物和超复合物构建的，这些复合物和超复合物分布在不同的突触中。突触蛋白的突变会改变突触组的结构，导致行为表型的改变。调节突触组层次组装的机制，包括转录和蛋白质稳态的突变，也可能改变突触的多样性和突触组的结构。突触组层次组装的逻辑提供了一个机制框架，解释了不同的遗传疾病如何在不同的大脑回路中集中在突触上，产生行为表型。
