Structural and functional studies of the VAPB-PTPIP51 ER-mitochondria tethering proteins in neurodegenerative diseases

神经退行性疾病中 VAPB-PTPIP51 ER 线粒体束缚蛋白的结构和功能研究

• 批准号: MR/X021858/1
• 负责人: Christopher Miller
• 金额: $ 138.04万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX021858%2F1
• 关键词: Structural; functional; studies; VAPB; PTPIP51

Alzheimer's disease and related dementias, and amyotrophic lateral sclerosis (ALS) are major neurodegenerative diseases that afflict large proportions of our population and exert huge burdens on our healthcare system and economy. There are no cures for any of these diseases and for Alzheimer's disease and ALS, there are not even effective disease modifying treatments. There is therefore an urgent need to identify new therapeutic targets for treating these diseases.Alzheimer's disease and ALS share several pathological features. These include damage to calcium concentrations in neurons, fat metabolism, mitochondria (the energy producers of the cell), transport of proteins and mitochondria within neurons, activation of cellular stress responses, alterations to a process termed autophagy which removes damaged proteins from neurons and damage to synapses which are the connections neurons make with each other to compute and relay signals. Finally, inflammation is seen in both diseases. The biological conundrum is how so many apparently disparate physiological processes are damaged collectively. The therapeutic challenge is selecting which of these different damaged processes to prioritize for drug discovery.Recently, attention has focused on how two components of neurons, the endoplasmic reticulum (ER) and mitochondria, communicate and signal to each other in neurodegenerative diseases. This is because ER-mitochondria signaling regulates all of the functions described above that are damaged in these diseases. We and others have shown that ER-mitochondria signaling is perturbed in Alzheimer's disease and ALS, and we have identified a mechanism that facilitates this communication. It involves binding of the ER protein VAPB to the mitochondrial protein PTPIP51; this binding acts to "tether" ER with mitochondria to facilitate signaling. We have gone on to show that the VAPB-PTPIP51 tethers are disrupted in some neurodegenerative diseases and that this involves activation of a kinase enzyme termed GSK3beta. We have also identified another kinase enzyme (AMP kinase) that stimulates VAPB-PTPIP51 binding. These kinases modify proteins to influence their function and interactions via a process termed phosphorylation. One hypothesis is that GSK3beta and AMP kinase phosphorylate VAPB and/or PTPIP51 to regulate their binding and that this is perturbed in neurodegenerative diseases. Disruption of VAPB-PTPIP51 binding and ER-mitochondria signaling then leads to synapse damage, neuronal cell death and neurodegenerative disease. The aims of this project are to test aspects of this hypothesis. The objectives are:1. To gain information on the structure of VAPB-PTPIP51 complexes since this knowledge will facilitate the design of drugs that can correct damaged tethers in neurodegenerative diseases.2. To identify GSK3beta/AMP kinase phosphorylation sites in VAPB and PTPIP51 and to determine how this effects their binding.3. To determine whether changes in VAPB and PTPIP51 phosphorylation occur in human post-mortem Alzheimer's disease and ALS tissues and in animal models of ALS.4. To determine whether experimental disruption of the VAPB-PTPIP51 tethers in animals leads to neurodegenerative disease.These findings will help us understand the role that the VAPB-PTPIP51 tethers play in Alzheimer's disease and ALS, and they will facilitate the design of potential therapeutics for neurodegenerative disease that target the VAPB-PTPIP51 interaction.

阿尔茨海默氏病和相关痴呆症以及肌萎缩性侧索硬化症（ALS）是主要的神经退行性疾病，其折磨我们大部分人口，并对我们的医疗保健系统和经济造成巨大负担。这些疾病中的任何一种都没有治愈方法，对于阿尔茨海默病和ALS，甚至没有有效的疾病修饰治疗。因此，迫切需要确定治疗这些疾病的新的治疗靶点。阿尔茨海默病和ALS有一些共同的病理特征。这些包括对神经元中钙浓度的损害，脂肪代谢，线粒体（细胞的能量产生者），神经元内蛋白质和线粒体的运输，细胞应激反应的激活，对称为自噬的过程的改变，其从神经元中去除受损的蛋白质，以及对突触的损害，突触是神经元相互连接以计算和传递信号。最后，炎症在这两种疾病中都可以看到。生物学上的难题是这么多明显不同的生理过程是如何共同受损的。治疗的挑战是选择这些不同的受损过程中优先药物发现。最近，人们的注意力集中在神经元的两个组成部分，内质网（ER）和线粒体，如何在神经退行性疾病中相互交流和信号。这是因为ER-线粒体信号传导调节上述在这些疾病中受损的所有功能。我们和其他人已经表明，ER-线粒体信号在阿尔茨海默病和ALS中受到干扰，我们已经确定了促进这种通信的机制。它涉及ER蛋白VAPB与线粒体蛋白PTPIP 51的结合;这种结合作用是将ER与线粒体“拴系”以促进信号传导。我们已经继续表明，VAPB-PTPIP 51系链在一些神经退行性疾病中被破坏，这涉及一种称为GSK 3 β的激酶的激活。我们还鉴定了另一种刺激VAPB-PTPIP 51结合的激酶（AMP激酶）。这些激酶修饰蛋白质以通过称为磷酸化的过程影响它们的功能和相互作用。一种假设是GSK 3 β和AMP激酶磷酸化VAPB和/或PTPIP 51以调节它们的结合，并且这在神经退行性疾病中受到干扰。VAPB-PTPIP 51结合和ER-线粒体信号传导的破坏然后导致突触损伤、神经元细胞死亡和神经退行性疾病。这个项目的目的是测试这个假设的各个方面。目标是：1.获得VAPB-PTPIP 51复合物的结构信息，因为这一知识将有助于设计可以纠正神经退行性疾病中受损栓系的药物。鉴定VAPB和PTPIP 51中的GSK 3 β/AMP激酶磷酸化位点，并确定这如何影响它们的结合.确定VAPB和PTPIP 51磷酸化的变化是否发生在人类死后阿尔茨海默病和ALS组织以及ALS动物模型中。为了确定在动物中实验性破坏VAPB-PTPIP 51系链是否会导致神经退行性疾病，这些发现将帮助我们了解VAPB-PTPIP 51系链在阿尔茨海默病和ALS中的作用，并且它们将促进针对VAPB-PTPIP 51相互作用的神经退行性疾病的潜在治疗方法的设计。