Ubiquitination as an acute regulator of synaptic transmission

描述(由申请人提供)：突触传递是神经系统的一个关键特征，因此在许多不同的时间尺度上都受到严格的调控。泛素-蛋白酶体系统(UPS)通过维持适当的蛋白质动态平衡，在突触传递中发挥重要作用。UPS通过塑造长期可塑性，通过改变活跃突触的数量和改变囊泡池的大小来调节发育过程中突触的形成。所有这些调节功能都在几小时到几天的时间尺度上发生，并与UPS在蛋白质降解中的核心作用一致：泛素标签蛋白的共价结合使蛋白质酶体降解。我们最近发现，UPS还在几分钟或更短的时间范围内调节神经递质的释放。这导致了我们的假设，即突触的泛素化通过改变靶蛋白的活性水平而不是改变它们的半衰期来快速调节释放。因此，蛋白质泛素化可以作为突触功能的急性动态调节。鉴于突触传递在神经系统功能中的核心作用，这代表了一种新的调控途径，具有明显的基础科学兴趣。然而，该途径也具有明显的临床意义，因为它可能提供对与神经退行性疾病相关的功能障碍的早期步骤的洞察。在许多神经退行性疾病中，突触功能障碍的迹象出现在临床症状之前。神经退行性疾病的特征也是UPS，它通过途径突变、蛋白质错误折叠或环境毒素受损。认识到UPS在形成突触传递中的快速调节作用可能提供UPS损伤和突触功能障碍之间的早期因果联系。在这项拨款申请中，我们将测试通过泛素化调节突触前释放的生理机制(目标1)。结合突触泛素组(AIM2)的鉴定，这些实验将使发现具有基础科学意义的途径和过程成为可能，并可能为神经系统疾病提供新的可用药靶点。

DESCRIPTION (provided by applicant): Synaptic transmission is a critical feature of the nervous system and is as such tightly regulated on many different time-scales. The ubiquitin-proteasome system (UPS) plays an important role in synaptic transmission by maintaining appropriate protein homeostasis. The UPS regulates synapse formation during development, by shaping long-term plasticity, by altering the number of active synapses and by changing the size of vesicle pools. All of these regulatory functions occur on a time scale of hours to days and are consistent with the central role of the UPS in protein degradation: covalent attachment of ubiquitin tags proteins for degradation by the proteasome. We have recently discovered that the UPS also regulates neurotransmitter release on a time-scale of a few minutes or less. This led us to the hypothesis that ubiquitination at the synapse rapidly regulates release by changing the activity level of target proteins rather than changing their half-life. Thus, protein ubiquitination can serve as an acute dynamic regulator of synaptic function. This represents a novel regulatory pathway that is of clear basic science interest given the central role of synaptic transmission in nervous system function. However, the pathway is also of clear clinical interest as it might offer insight into the earliest steps of dysfunction associated with neurodegenerative diseases. In many neurodegenerative diseases signs of synaptic dysfunction precede clinical symptoms. Neurodegenerative diseases are also characterized by a UPS that is impaired either through mutations in the pathway, by misfolded proteins or via environmental toxins. The recognition of the rapid regulatory role of the UPS in shaping synaptic transmission might offer an early causal link between UPS impairment and synaptic dysfunction. In this grant application we will test the physiological mechanisms that mediate the rapid regulation of presynaptic release by ubiquitination (Aim 1). Together with the identification of the synaptic ubiquitome (Aim2) these experiments will enable discovery of pathways and processes that are of basic science interest and that might provide novel druggable targets for neurological diseases.