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

该学生将开发可用于有效阻断导致帕金森病（PD）病理的有毒蛋白质形成的肽。这种被称为α -突触核蛋白（as）的蛋白质在大脑中产生多巴胺的细胞内自我结合，形成被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构建（Meade等人J Mol Biol 2021, 2022， Watt等人ACS Chem Neurosci 2022， Watt等人J Biol Chem 2022）。使用一种新颖的筛选系统，针对aS的自然折叠状态，即在错误折叠和聚集之前，该学生将筛选活细菌细胞内的大型肽库（bbb20万个成员）。在这个实验中，只有当聚集的第一步被阻断，导致细胞活力的恢复时，才会选择抑制剂。该学生将使用筛选试验生成许多抑制肽来阻止aS错误折叠的第一步。这将提供广泛的序列，从中我们可以通过生物物理、神经元细胞和结构生物学方法了解抑制机制。我们的首要目标是在我们新生成的抑制剂中为特定序列元素分配功能，以证明合理抑制剂设计的原则，最终改善未来肽代的特性。最后，通过比较内源性肽和外源性肽，学生将开始探索药物传递的各个方面，例如到达细胞内靶点的渗透性。监督团队的组成确保了在这个跨学科项目的各个方面都有全面的专业知识。培训环境将是高度支持和激励的，包括与科学界更广泛接触的充分机会。您将被引导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。

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.