Coordination Funds

协调基金

• 批准号: 466405351
• 负责人: Dr. Michael R. Kreutz
• 金额: --
• 依托单位: Forschungsgruppe Neuroplastizität
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/466405351?language=en
• 关键词: Coordination; Funds

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?

神经元是具有复杂细胞结构的极化细胞。通常情况下，突触的数量是巨大的，它们的分子组成非常复杂，而且它们与细胞体的距离可能是巨大的，而细胞体是大多数蛋白质合成发生的地方。由于神经元是有丝分裂后的，而且寿命长，因此保持其蛋白质组的完整性特别重要。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，因此突触前代表了高能量需求和高度活跃的膜动力学区域。轴突和轴突终末的蛋白质周转是如何调节的，以及这是发生在局部（即突触）还是发生在索马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）。我们的知识缺口涉及哪些降解途径，蛋白质如何为某些降解机制分类，分类本身是如何完成的，不同的途径如何有助于突触前蛋白质组，信号引导蛋白质进入给定的途径，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”。我们也缺乏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）的需要相互联系的透彻理解。因此，现在是处理这一长串未决问题和未决问题的时候了。为了实现这一目标，我们组建了一个由突触生物学家组成的专家团队，他们将为突触前蛋白质稳态问题贡献不同的方法和能力。该团队包括来自柏林、马格德堡和海法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，标志着一个超级加性团队。我们的使命将是通过解决以下问题来开辟新的领域：自噬、蛋白酶体介导的和内溶酶体降解对突触前蛋白稳态的具体贡献是什么？突触前功能以及重要的可塑性是如何被自噬调节的？自噬在局部是如何调节的？最后，自噬体的非规范功能（例如信号传导）如何影响突触前发育，维持和功能？