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

总结 我们对认知和行为障碍的分子机制的理解不足 FTD的特征是确定有效治疗的关键障碍。该项目将寻求 通过研究SUMO化（一种翻译后修饰，我们的实验室 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 和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。 SUMO化，11 kDa SUMO（小泛素样调节剂）的共价和可逆连接 在Tau聚集和线粒体动力学中涉及蛋白质与靶蛋白质的相互作用。有 在脊椎动物脑中有三个已知的SUMO旁系同源物，SUMO 1 -3，其中SUMO 2和3共享约95%的序列 同源性（并且没有功能性分化）通常统称为SUMO 2/3。相扑1 先前报道与Tau缀合促进其聚集和错误定位，我们发现， SUMO 2缀合减少Tau聚集并恢复其在神经元中的正常分布。而且我们 发现表达Tau突变P301 S的FTD动物模型（PS19小鼠）显示：1） 线粒体呼吸链酶（RCE）活性，以及受损的突触功能（LTP）;和2） 增加的SUMO 1-结合和减少的SUMO 2-结合。最重要的是，SUMO 2的过表达改善了 体外RCE活动，以及体内LTP和记忆。此外，用生物可利用的 促进SUMO 2结合的多肽（BioSenA），在FTD小鼠中挽救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蛋白导致线粒体 功能障碍，导致异常SUMO化和突触缺陷;增加SUMO 2 结合通过阻止线粒体中oTau诱导的缺陷，以及突触功能和记忆， Tau聚集。我们将测试我们的假设与以下三个具体目标：1。确定因果 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 SUMO 1的过表达对线粒体/突触功能具有不利影响; 3.测试是否 SUMO 2的过表达挽救了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、生物物理学和生物化学的组合来解决 在野生型和遗传修饰小鼠以及FTD患者的iPSC衍生神经元中使用的技术。 在完成这些实验后，我们将确定SUMO化控制细胞凋亡的机制。 FTD中tau相关损伤的发生，并检测靶向SUMO 2的干预措施 缀合可构成其治疗的有效治疗方法。

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.