ANALYSIS OF ZDHHC17 INTERACTION NETWORKS AND PROTEIN INTERACTIONS LINKED TO NEURODEGENERATION

我们体内的细胞含有多种不同的蛋白质，它们协调和驱动特定的途径，比如大脑中的神经元交流。这些蛋白质通常受到严格调控，以确保它们在所需的空间和时间方式下执行其特定功能。调节蛋白质功能的一种主要方式是通过对氨基酸主链进行特定的化学修饰，并在蛋白质中添加各种不同的化学基团来影响它们的活性。一种重要但鲜为人知的修饰是“s -酰化”，即脂肪酸附着在蛋白质上。细胞蛋白的s -酰化是由24个“zDHHC”酶家族催化的。zDHHC酶功能障碍与神经退行性疾病、精神分裂症和智力残疾等疾病之间的联系强调了这些酶对正常脑功能的重要性。尽管zDHHC酶很重要，但我们缺乏关于该蛋白家族的基本知识，包括单个酶同种异构体的底物相互作用网络，这些相互作用的变化如何促进疾病病理，以及这些相互作用如何作为治疗策略的靶向。我们小组最近的工作在这一领域提供了一个重要的突破，通过鉴定被酶zDHHC17识别的特定蛋白质序列；这种酶对大脑功能至关重要，并与特定的神经退行性疾病有关。在本项目中，我们将利用我们关于zDHHC17识别序列的新发现来鉴定该酶在神经元中的底物相互作用网络，为我们了解zDHHC17的生理功能提供重大进展。此外，我们将研究zDHHC17与其关键底物之一亨廷顿蛋白的相互作用如何在亨廷顿病中受到影响，为这种神经退行性疾病的发病机制提供新的见解。最后，我们将利用zDHHC17识别序列的新信息来开发可能具有治疗神经退行性疾病神经元类脂褐质病潜力的化合物。总的来说，这些专注于zDHHC17识别序列的研究将为zDHHC17的生理功能、其与亨廷顿病的联系以及该酶作为神经元类脂褐质病新治疗靶点的潜力提供新的信息。

The cells in our body contain a diverse array of different proteins that coordinate and drive specific pathways, such as neuronal communication in the brain. These proteins are often tightly regulated to ensure that they perform their specific functions in the required spatial and temporal manner. A major way of regulating protein function is by specific chemical modifications that are made to the amino acid backbone, and a variety of different chemical groups are added to proteins that affect their activity. One important but poorly understood modification is "S-acylation", the attachment of fatty acids onto proteins. S-acylation of cellular proteins is catalysed by a family of twenty-four "zDHHC" enzymes. The importance of these enzymes for normal brain function is underscored by reported links between zDHHC enzyme dysfunction and conditions such as neurodegeneration, schizophrenia, and intellectual disability.Despite the importance of zDHHC enzymes, we lack fundamental knowledge about this protein family, including the substrate interaction networks of individual enzyme isoforms, how changes in these interactions contribute to disease pathology, and how these interactions can be targeted as a therapeutic strategy. Recent work from our group has provided an important breakthrough in this area by identifying a specific protein sequence that is recognised by the enzyme zDHHC17; this enzyme is essential for brain function and is associated with specific neurodegenerative disorders. In this project, we will exploit our new findings about the zDHHC17 recognition sequence to identify the substrate interaction network of this enzyme in neurons, providing a major advance in our understanding of the physiological functions of zDHHC17. In addition, we will investigate how the interaction of zDHHC17 with one of its key substrates, huntingtin, is affected in Huntington's disease to provide new insight into the pathogenesis of this neurodegenerative disorder. Finally, we will employ the novel information on the zDHHC17 recognition sequence to develop compounds that may have potential for the treatment of the neurodegenerative disease, neuronal ceroid lipofuscinosis. Collectively, these studies focused on the zDHHC17 recognition sequence will provide new information on the physiological functions of zDHHC17, its links with Huntington's disease, and the potential of this enzyme to serve as a novel therapeutic target for neuronal ceroid lipofuscinosis.