Ordering the disordered in Parkinson's disease to derive peptide inhibitors of alpha-synuclein toxicity

学生将开发肽，可用于有效地阻止形成一种有毒蛋白质负责帕金森病（PD）的病理。这种蛋白质被称为α-突触核蛋白（aS），在大脑中产生多巴胺的细胞内自我缔合，形成称为路易体的有毒团块，干扰正常的大脑功能，导致疾病的症状。我们将从我们已经证明有效的系统中抑制该过程的建立（米德等人J Mol Biol 2021，2022，Watt等人ACS Chem Neurosci 2022，Watt等人J Biol Chem 2022）。使用一种新的筛选系统，目标是在错误折叠和聚集之前的aS的自然折叠状态，学生将筛选活细菌细胞内的大型肽库（> 200万成员）。在该测定中，仅当聚集的第一步被阻断，导致细胞活力恢复时才选择抑制剂。学生将使用筛选试验来产生许多抑制肽来阻断aS折叠的最初步骤。这将提供广泛的序列，我们可以通过生物物理学，神经元细胞为基础的，和结构生物学方法来理解抑制机制。我们的首要目标是在我们新产生的抑制剂中将功能分配给特定序列元件，以证明合理的抑制剂设计的原则，最终改善未来肽代的特性。最后，借由比较内源性产生的胜肽与外部添加的胜肽，学生将开始探索药物输送的各个方面，例如到达细胞内目标的渗透性。监督团队的组成确保了这个跨学科项目各个方面的全面专业知识。培训环境将具有高度的支持性和激励性，包括提供与科学界更广泛接触的充分机会。你将通过这个项目的挑战和回报，同时获得广泛的技能，可翻译到许多其他系统的指导。

The student will develop peptides that can be used to effectively block formation of a toxic protein responsible for thepathology of Parkinson's disease (PD). The protein, known as alpha-synuclein (aS), self-associates inside dopamineproducing cells in the brain to form toxic clumps known as Lewy bodies that interfere with normal brain function, leadingto the symptoms of the disease. We will inhibit this process building from a system that we have demonstrated to work(Meade et al J Mol Biol 2021, 2022, Watt et al ACS Chem Neurosci 2022, Watt et al J Biol Chem 2022). Using a novelscreening system that targets the natural folded state of aS, that is prior to misfolding and aggregation, the student willscreen large peptide libraries (>2 Million members) inside living bacterial cells. In this assay, inhibitors are only selected ifthe very first step in aggregation is blocked, leading to a restoration of cell viability. The student will use the screening assay to generate numerous inhibitory peptides to block the very first steps in themisfolding of aS. This will provide a wide range of sequences from which we can understand the mechanism of inhibitionvia biophysical, neuronal cell-based, and structural biology methods. Our overarching aim is to assign function to specificsequence elements within our newly generated inhibitors to demonstrate the principles of rational inhibitor design,ultimately improving the properties of future peptide generations. Finally, by comparing endogenously produced toexternally added peptides, the student will begin to explore aspects of drug delivery, such as permeability to reachintracellular targets. The composition of the supervisory team ensures comprehensive expertise in all facets of thisinterdisciplinary project. The training environment will be highly supportive and stimulating, including ampleopportunity for wider engagement with the scientific community. You will be guided through the challenges andrewards of this project while gaining a wide range of skills that are translatable to many other systems.