Role of SUMOylation in Mitochondrial/Synaptic Axis Dysfunction Induced by Abnormal Tau in FTD

SUMO 化在 FTD 异常 Tau 诱导的线粒体/突触轴功能障碍中的作用

基本信息

批准号：
10779264
负责人：
LUANA FIORITI
金额：
$ 70.99万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2023-09-19 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10779264
关键词：
Address Affect Alzheimer&apos s Disease Animal Model Antioxidants Behavioral Biochemical Biological Availability Biophysics Brain Cells Cognitive Data Defect Dementia Development Disease Electrophysiology (science)Enzymes Frontotemporal Dementia Functional disorder Hippocampus Impaired cognition Impairment In Vitro Induced pluripotent stem cell derived neurons Intervention Knowledge Laboratory Finding Link Measures Mediating Memory Memory Loss Messenger RNA Mitochondria Modeling Molecular Mus Neurons Normal Statistical Distribution Oxidative Stress Pathologic Patients Post-Translational Protein Processing Production Proteins Reporting Respiratory Chain Role SUMO1 gene Sequence Homology Series Sumoylation Pathway Synapses Synaptic Transmission Synaptic plasticity Tauopathies Techniques Testing Time Toxic effect Ubiquitin Wild Type Mouse behavioral impairment effective therapy enzyme activity experimental study improved in vitro activity in vivo induced pluripotent stem cell mitochondrial dysfunction overexpression paralogous gene polypeptide prevent protein aggregation synaptic function tau Proteins tau aggregation tau mutation therapeutic target therapeutically effective

项目摘要

Summary Our poor understanding of the molecular mechanisms that underlie the cognitive and behavioral impairments that characterize FTD stands as a critical barrier to identifying effective treatments. This project will seek to address this gap in knowledge by examining how SUMOylation, a post-translational modification that our labs found to be impaired in FTD models, controls Tau aggregation and pathological action of Tau on mitochondrial and synaptic functions in animal models as well as patient-derived neurons associated with Tau mutations. SUMOylation, the covalent and reversible attachment of an 11 kDa SUMO (Small Ubiquitin-like MOdifier) protein to target proteins, has been implicated in both Tau aggregation and mitochondrial dynamics. There are three known SUMO paralogs in vertebrate brains, SUMO1-3, with SUMO2 and 3 sharing ~95% sequence homology (and not functionally differentiated) often collectively referred to as SUMO2/3. While SUMO1 conjugation to Tau was previously reported to promote its aggregation and mislocalization, we found that SUMO2 conjugation reduces Tau aggregation and restores its normal distribution in neurons. Moreover, we found that animal models of FTD, expressing the Tau mutations P301S (PS19 mice) show: 1) deficits in mitochondrial respiratory chain enzymes (RCE) activities, as well as impaired synaptic function (LTP); and 2) increased SUMO1- and reduced SUMO2- conjugation. Most importantly, overexpression of SUMO2 improved RCE activities in vitro, as well as LTP and memory in vivo. Furthermore, treating mice with a bioavailable polypeptide that promotes SUMO2 conjugation (BioSenA), rescued LTP and memory loss in FTD mice. Based on these preliminary results, we hypothesize that aggregated and mislocalized Tau causes mitochondrial dysfunction, which results in aberrant SUMOylation and synaptic deficits; and that increasing SUMO2 conjugation rescues oTau-induced defects in mitochondria, and synaptic function and memory, by preventing Tau aggregation. We will test our hypotheses with the following three specific aims: 1. Determine the causal relationship between SUMO conjugation and Tau-induced mitochondrial dysfunction; 2. Test whether overexpression of SUMO1 has a detrimental effect on mitochondrial/synaptic function; 3. Test whether overexpression of SUMO2 rescues the mitochondrial/synaptic axis dysfunction in FTD models. These aims will be addressed through a combination of electrophysiological, behavioral, biophysical, and biochemical techniques in wild-type and genetically modified mice as well as iPSC-derived neurons from FTD patients. Upon the completion of these experiments, we will identify the mechanisms whereby SUMOylation controls the development of tau-related impairments in FTD, and test the possibility that interventions that target SUMO2 conjugation could constitute an effective therapeutic approach for their treatment.

概括我们对认知和行为障碍背后的分子机制了解甚少 FTD 的特征是确定有效治疗方法的关键障碍。该项目将寻求通过研究 SUMOylation（我们的实验室的一种翻译后修饰）如何解决这一知识空白在 FTD 模型中发现受损，控制 Tau 聚集和 Tau 对线粒体的病理作用动物模型中的突触功能以及与 Tau 突变相关的患者来源的神经元。 SUMOylation，11 kDa SUMO（小泛素样修饰剂）的共价和可逆连接蛋白质到目标蛋白质，与 Tau 聚集和线粒体动力学有关。有脊椎动物大脑中三个已知的 SUMO 旁系同源物 SUMO1-3，其中 SUMO2 和 3 共享约 95% 的序列同源性（并且没有功能区分）通常统称为 SUMO2/3。而相扑1 之前有报道称与 Tau 的结合会促进其聚集和错误定位，我们发现 SUMO2 结合可减少 Tau 聚集并恢复其在神经元中的正常分布。此外，我们发现表达 Tau 突变 P301S（PS19 小鼠）的 FTD 动物模型显示：1）线粒体呼吸链酶（RCE）活性以及突触功能（LTP）受损；和 2) 增加 SUMO1- 并减少 SUMO2- 缀合。最重要的是，SUMO2 的过度表达改善了体外 RCE 活性，以及体内 LTP 和记忆。此外，用生物可利用的药物治疗小鼠促进 SUMO2 结合的多肽 (BioSenA)，挽救了 FTD 小鼠的 LTP 和记忆丧失。基于根据这些初步结果，我们假设聚集和错误定位的 Tau 蛋白会导致线粒体功能障碍，导致 SUMO 化异常和突触缺陷；并且增加 SUMO2 接合通过防止 oTau 诱导的线粒体、突触功能和记忆缺陷 Tau 蛋白聚集。我们将通过以下三个具体目标来检验我们的假设： 1. 确定因果关系 SUMO 结合与 Tau 诱导的线粒体功能障碍之间的关系； 2、测试是否 SUMO1 的过度表达对线粒体/突触功能有不利影响； 3、测试是否 SUMO2 的过度表达可挽救 FTD 模型中的线粒体/突触轴功能障碍。这些目标将通过电生理学、行为学、生物物理和生物化学的结合来解决该技术适用于野生型和转基因小鼠以及来自 FTD 患者的 iPSC 衍生神经元。完成这些实验后，我们将确定 SUMOylation 控制的机制 FTD 中 tau 相关损伤的发展，并测试针对 SUMO2 的干预措施的可能性结合可以构成治疗它们的有效治疗方法。