The Role of SUMOylation in Tau-Mediated Pathology

我们对认知和行为障碍的分子机制的理解不足 阿尔茨海默病的特征是确定有效治疗阿尔茨海默病的关键障碍 疾病本项目旨在通过检查SUMO化的能力来解决我们理解中的这一差距， 翻译后修饰，在此过程中，小肽称为小泛素样修饰剂（SUMO） 共价连接到靶底物上的赖氨酸残基，以控制tau - a中枢的病理作用。 在疾病的分子病因学的组成部分。SUMO化是一个可逆的过程，对 蛋白质功能，包括许多细胞蛋白质的定位、稳定性和活性的调节，以及 核完整性、染色体分离和基因表达。有三个已知的相扑旁系同源， 脊椎动物脑：SUMO 1 -3，与SUMO 2和3共享~95%的序列同源性（而非功能性 通常统称为SUMO 2/3。有趣的是，SUMO化在细胞中失调， 阿尔茨海默病患者的海马体。在初步研究中，我们已经能够将tau蛋白SUMO化 与tau聚集和SUMO 2缀合（但不是SUMO 1）的毒性相关， 和毒性。还发现SUMO 2减少聚集的tau释放。此外，模拟SUMO 2共价键， 与tau蛋白的结合挽救了寡聚体tau蛋白诱导的长时程增强（LTP）损伤，LTP是一种突触 可塑性被认为是记忆形成的基础，以及额颞叶痴呆小鼠模型的记忆丧失。 在本提案中，我们将以这些观察结果为基础，追求以下具体目标：1）确定 上调SUMO 2缀合挽救了tau诱导的突触功能缺陷; 2）确定上调SUMO 2缀合是否 SUMO 2缀合在小鼠中拯救tau诱导的记忆缺陷; 3）测试SUMO 2缀合的拯救作用是否与小鼠的记忆缺陷有关。 上调SUMO 2缀合依赖于tau寡聚体形成的调节。这些目标将是 通过电生理学、行为学、生物物理学和生物化学技术的组合来解决 在野生型和转基因小鼠中。在这些实验完成后，我们将确定 SUMO化控制阿尔茨海默病中tau相关损伤发展的机制 和额颞叶痴呆，并测试靶向SUMO 2结合的干预可能性， 这是一种有效的治疗方法。

Our poor understanding of the molecular mechanisms that underlie the cognitive and behavioral impairments that characterize Alzheimer’s disease stands as a critical barrier to identifying effective treatments for Alzheimer’s disease. This project seeks to address this gap in our understanding by examining the ability of SUMOylation, a post-translational modification during which small peptides called small ubiquitin-like modifiers (SUMOs) covalently attach to lysine residues on target substrates, to control the pathological actions of tau – a central component in the molecular etiology of the disease. SUMOylation is a reversible process with various effects on protein function, including regulation of localization, stability and activity of many cellular proteins, as well as nuclear integrity, chromosomal segregation and gene expression. 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. Interestingly, SUMOylation is dysregulated in the hippocampus of Alzheimer’s Disease patients. In preliminary studies we have been able to link tau SUMOylation to tau aggregation and toxicity with SUMO2 conjugation (but not SUMO1) protecting against tau aggregation and toxicity. SUMO2 was also found to decrease aggregated tau release. Moreover, mimicking SUMO2 covalent binding to tau rescued the oligomeric tau-induced impairment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation, and memory loss in a mouse model of fronto-temporal dementia. In this proposal, we will build on these observations by pursuing the following specific aims: 1) determine if upregulating SUMO2 conjugation rescues tau-induced defects in synaptic function; 2) determine if upregulating SUMO2 conjugation rescues tau-induced memory defect in mice; 3) test whether the rescuing effects of upregulating SUMO2 conjugation depend upon modulation of tau oligomer formation. These aims will be addressed through a combination of electrophysiological, behavioral, biophysical, and biochemical techniques in wild-type and genetically modified mice. Upon the completion of these experiments, we will identify the mechanisms whereby SUMOylation controls the development of tau-related impairments in Alzheimer’s disease and in fronto-temporal dementia, and test the possibility that interventions that target SUMO2 conjugation could constitute an effective therapeutic approach for their treatment.