ATase1 and ATase2, proteostasis, and neurological diseases

ATase1 和 ATase2、蛋白质稳态和神经系统疾病

基本信息

批准号：
10554962
负责人：
Luigi Puglielli
金额：
$ 30.03万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10554962
关键词：
Acetyl Coenzyme A Acetylation Acetyltransferase Animals Autophagocytosis Biochemical Biological Process Biology Brain Cellular biology Cessation of life Collaborations Communication Deacetylase Defect Developmental Delay Disorders Endoplasmic Reticulum Ensure Equilibrium Event Functional disorder Gene Duplication Genetic Glutamate-ammonia-ligase adenylyltransferase Glycoproteins Goals Golgi Apparatus Heterozygote Human Intellectual functioning disability Laboratories Lysine Maintenance Mass Spectrum Analysis Mediating Membrane Transport Proteins Metabolic Modeling Molecular Molecular Biology Mus Mutation Neurons Neuropathy Organelles Output Pathway interactions Peripheral Phenotype Progeria Proteins Quality Control Research Series Techniques Testing Therapeutic autism spectrum disorder design disease phenotype experimental study human disease in vivo loss of function mouse model nervous system disorder novel pharmacologic premature protein aggregation proteostasis response trafficking translational approach

项目摘要

We discovered that Nε-lysine acetylation occurs in the lumen of the endoplasmic reticulum (ER) in 2007. From that initial finding, we went on to discover the entire ER acetylation machinery (one membrane transporter, AT-1/SLC33A1, and two acetyltranferases, ATase1 and ATase2) and uncover a novel piece of ER biology. Specifically, we discovered that the ER acetylation machinery regulates proteostasis within the secretory pathway as well as metabolic crosstalk between different intracellular organelles and compartments. Human-based studies discovered that dysfunctional ER acetylation, as caused by loss-of-function homozygous and heterozygous mutations or gene duplication events, is associated with different human diseases, from developmental delay of the brain and premature death to peripheral forms of neuropathy, autism spectrum disorder, intellectual disability and segmental progeria. Mouse models that mimic these genetic events recapitulate associated human diseases. Importantly, ATase-targeting compounds that restore the proteostatic functions of the ER rescue the disease phenotypes of the animals. In conclusion, we have identified a novel molecular machinery that is key to the maintenance of proteostasis within the secretory pathway, and that can be targeted to (i) understand the pathophysiology of several related neurological diseases and (ii) develop appropriate translational approaches to resolve proteostatic defects. The GENERAL HYPOTHESIS of this research is that ATase1 and ATase2 act downstream of an intracellular communication network that regulates the proteostatic functions of the ER and secretory pathway. Our main goal is to dissect the molecular mechanism(s) underlying the acetyl-CoA:lysine acetyltransferase activity of the ATases and understand how ER-based acetylation regulates the efficiency of the secretory pathway. Aim 1 will test the hypothesis that the ATases have divergent functions and differentially regulate proteostasis and metabolic crosstalk. Aim 2 will test the hypothesis that unique structural features allow the ATases to respond to acetyl-CoA influx, Ca++ levels, and perturbations in ER proteostasis. Aim 3 will test the hypothesis that the acetyl group added in the ER lumen by the ATases must be removed in the lumen of the Golgi apparatus by Amfion/GDAC to ensure correct trafficking of nascent glycoproteins and the quality of the secretome. In conclusion, this proposal is based on novel findings from our laboratory and offers a series of highly mechanistic studies that have the potential to define new avenues of research (and treatment) for different neurological diseases. The proposal will use unique mouse models as well as highly integrated novel experimental approaches. We believe that upon completion of these studies, we will have defined an entirely new avenue of research for different neurological diseases.

我们发现Nε-赖氨酸乙酰化发生在2007年的内质网（ER）的腔内。从最初的发现，我们继续发现了整个ER乙酰化机械（一个膜转运蛋白，AT-1/SLC33A1，AT-1/SLC33A1，以及两个乙酰磷酸酶，Atase1和atase1和Atase2和Atase2）和一件小说。具体而言，我们发现ER乙酰化机械调节秘书途径内的蛋白质量，以及不同细胞内细胞器和隔室之间的代谢串扰。基于人类的研究发现，功能失调的ER乙酰化是由纯合和杂合突变丧失引起的，或基因重复事件与不同的人类疾病有关，来自不同的人类疾病，从发展大脑的延迟到过早死亡到神经病，自闭症谱，智力疾病，知识疾病，知识疾病，智力疾病，智力疾病，智力疾病和片段的外周形式。模仿这些遗传事件的小鼠模型概括了相关的人类疾病。重要的是，恢复ER的蛋白抑制功能的靶向化合物营救了动物的疾病表型。总之，我们已经确定了一种新型的分子机械，该机械是维持秘密途径中蛋白质量的关键，并且可以针对（i）了解几种相关神经系统疾病的病理生理学，并且（ii）开发了适当的翻译方法来解决蛋白质静态缺陷。这项研究的一般假设是，ATASE1和ATASE2在细胞内通信网络的下游调节ER和秘密途径的蛋白抑制功能。我们的主要目的是剖析乙酰辅酶A的分子机制：ATases的赖氨酸乙酰转移酶活性，并了解基于ER的乙酰基如何调节秘密途径的效率。 AIM 1将检验ATases具有不同功能的假设，并且对蛋白质量和代谢串扰的调节。 AIM 2将检验以下假设：独特的结构特征使Atases可以对ER蛋白质的乙酰-COA影响，Ca ++水平和扰动做出反应。 AIM 3将检验以下假设：必须通过AMFION/GDAC在高尔基体腔中除去Atases中添加的乙酰基群，以确保对新生糖蛋白的正确运输和秘密的质量进行正确的运输。总之，该提案基于我们实验室的新发现，并提供了一系列高度机理的研究，这些研究有可能定义不同神经疾病的研究（和治疗）的新途径。该提案将使用独特的小鼠模型以及高度集成的新型实验方法。我们认为，完成这些研究后，我们将定义针对不同神经疾病的全新研究途径。