The ubiquitin proteasome system as a regulator of neuronal function

受损和错误折叠的蛋白质的积累对细胞是有毒的，被认为是神经元老化和神经退行性疾病(如阿尔茨海默病和肌萎缩侧索硬化症)的主要原因。为了维持蛋白质的动态平衡，细胞有蛋白质降解途径来修复或移除受损的蛋白质。针对受损蛋白质的降解主要是由泛素蛋白酶体系统(UPS)介导的。重要的是，E3连接酶的特定亚型组成了UPS的关键部分，已知定位于神经元内。E3连接酶活性的丧失和由此引起的蛋白质稳态的紊乱被认为是神经元老化和神经变性的原因之一。有趣的是，越来越多的证据表明，这些蛋白质也是健康神经系统中神经功能的关键调节器。例如，UPS已被证明可以调节轴突的生长、突触的形成和神经递质的释放。然而，我们相对了解E3连接酶在活体内如何影响脊椎动物神经元。该项目将使用斑马鱼，一种用于体内神经科学研究的强大脊椎动物模型，以了解UPS的分子和药物扰动如何影响神经组织的生理功能、形态、连通性和输出。

The accumulation of damaged and misfolded proteins is toxic to cells and is believed to play a major role in neuronal ageing and neurodegenerative disorders such as Alzheimer's disease and Amyotrophic Lateral Sclerosis. In order to maintain protein homeostasis cells have protein degradation pathways which serve to repair or remove damaged proteins. The targeting of damaged proteins for degradation is primarily mediated by the Ubiquitin Proteasome System (UPS). Importantly, specific isoforms of the E3 ligases, which comprise a key part of the UPS, are known to localise within neurons. The loss of E3 ligase efficacy and the resultant perturbation of protein homeostasis is believed to contribute to neuronal ageing and neurodegeneration. Intriguingly, there is mounting evidence that these proteins also serve as key modulators of neuronal function in the healthy nervous system. For example, the UPS has been shown to regulate the grown of axons, the formation of synapses and the release of neurotransmitter. However, we know relatively about how E3 ligases influence vertebrate neurons in vivo. This project will use zebrafish, a powerful vertebrate model for in vivo neuroscience research, to understand how molecular and pharmacological perturbation of the UPS influences the physiology function, morphology, connectivity and output of neural tissue.