Coordination Funds

神经元是具有复杂细胞结构的极化细胞。一般来说，突触的数量是巨大的，它们的分子组成非常复杂，而且它们与大多数蛋白质合成发生的细胞体之间的距离可能很大。因为神经元都是有丝分裂后和长期存在的，保持其蛋白质组的完整性是特别重要的。在前脑突触中可以发现数百种不同的蛋白质，这种复杂的蛋白质组在蛋白质交换和周转的分子动力学方面创造了一种独特的情况，特别是在突触前。由于突触传递，轴突末端的局部膜交换异常高，因此突触前是一个高能量需求和高度活跃的膜动力学区域。轴突和轴突末端如何调节蛋白质周转，以及这是发生在局部（即突触）还是发生在体细胞中是一个关键的细胞生物学问题。目前，关于突触前蛋白质替代的必要性和机制的数据令人惊讶地缺乏（图1）。我们的知识差距涉及哪些降解途径，蛋白质如何为某些降解机制分类，分类本身如何完成，不同的途径如何促进突触前蛋白质组，哪些信号将蛋白质直接进入给定的途径，突触活动如何影响降解，如何调节串扰，以及哪些突触前传感器机制识别蛋白质“损伤”。我们对蛋白质降解的不同模式如何与蛋白质补充（即蛋白质生物合成）的需要相互联系也缺乏透彻的了解。因此，解决这一长串尚未解决的问题和悬而未决的问题是及时的。为了实现这一目标，我们组建了一个专业的突触生物学家团队，他们将为突触前蛋白质静止问题提供不同的方法和能力。该团队包括来自柏林、马格德堡和海法以色列理工学院的研究人员，他们(i)涵盖了广泛的技术，（ii）处于分子神经科学研究的技术前沿，（iii）显示出协同潜力，标志着一个超级添加剂团队。在我们的共同努力下，我们的任务将是通过解决以下问题来开辟新的领域：自噬、蛋白酶体介导和内溶酶体降解对突触前蛋白质停滞的具体贡献是什么？突触前功能和可塑性是如何被自噬调节的？自噬是如何受到局部调控的？最后，自噬体的非规范功能（如信号传导）如何影响突触前发育、维持和功能？

Neurons are polarized cells with a complex cytoarchitecture. Typically, the number of synapses is huge, their molecular makeup extraordinarily complex, and their distance from the cell body, where most protein synthesis occurs, can be enormous. Because neurons are both postmitotic and long-lived, maintaining the integrity of their proteome is of particular importance. Several hundred different proteins can be found in forebrain synapses and this complex proteome creates a unique situation with respect to the molecular dynamics of protein exchange and turnover, in particular at the presynapse. Due to synaptic transmission, local membrane exchange is exceptionally high at axonal terminals and accordingly the presynapse represents a region of high energy demand and highly active membrane dynamics. How protein turnover is regulated in axons and axon terminals, and whether this occurs locally (i.e. at the synapse) or in the soma is a key cell biological question. Currently, there is a surprising paucity of data on necessities for and mechanisms of protein replacement at presynapses (Fig. 1). Gaps in our knowledge concern which degradative pathways are involved, how proteins are sorted for certain degradative mechanisms, how sorting itself is accomplished, how different pathways contribute to the presynaptic proteome, which signals direct proteins into a given pathway, how synaptic activity affects degradation, how cross-talk is regulated, and which presynaptic sensor mechanisms identify protein 'damage'. We also lack a thorough understanding on how the different modes of protein degradation interconnect with the need for protein replenishment, i.e. protein biosynthesis. It is thus timely to address this long list of unresolved issues and open questions. To accomplish this goal, we assembled a team of expert synaptic biologists who will contribute different methodologies and competences to the problem of presynaptic proteostasis. The Team includes researchers from Berlin, Magdeburg and the Technion in Haifa that (i) cover a broad range of techniques, (ii) are at the technological forefront in molecular neuroscience research, and (iii) display synergistic potential to mark for a super-additive team. In a joint effort our mission will be to break new ground by addressing the following questions: What are the specific contributions of autophagy, proteasome-mediated and endo-lysosomal degradation to presynaptic proteostasis? How are presynaptic function and, importantly, plasticity regulated by autophagy? How is autophagy regulated locally? And, finally, how do non-canonical functions of autophagosomes (e.g. signalling) impact on presynaptic development, maintenance and function?