The role of SUMOylation in Tau-mediated pathology

我们对认知和行为障碍背后的分子机制缺乏了解 阿尔茨海默病的特征是寻找有效治疗阿尔茨海默氏症的关键障碍 疾病。这个项目试图通过检查SUMO化的能力来解决我们理解中的这个差距，一个 翻译后修饰，在此过程中，小肽被称为小泛素样修饰物(SUMO) 共价连接到靶底物上的赖氨酸残基上，控制tau-a中心的病理行为 在疾病的分子病因学中的组成部分。相加是一个可逆的过程，对 蛋白质功能，包括调节许多细胞蛋白质的定位、稳定性和活性，以及 核完整性、染色体分离和基因表达。在中国有三个已知的相扑选手 脊椎动物大脑：SUMO1-3，与SUMO2和3有~95%的序列同源性(而不是功能上的 分化)通常统称为SUMO2/3。有趣的是，SUMO化在 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糖基化 使用SUMO2结合(但不是SUMO1)保护tau聚集，以防止tau聚集和毒性 和毒性。SUMO2还可以减少tau的聚集释放。此外，模拟SUMO2共价 与tau结合挽救了tau寡聚体引起的突触长时程增强(LTP)损伤 可塑性被认为是额颞叶痴呆小鼠记忆形成和记忆丧失的基础。 在这项提案中，我们将以这些观察为基础，追求以下具体目标：1)确定是否 上调SUMO2结合挽救tau引起的突触功能缺陷；2)确定是否上调 SUMO2偶联修复tau诱导的小鼠记忆障碍；3)检测苏木精对Tau诱导的小鼠记忆障碍的修复作用 上调SUMO2结合依赖于tau齐聚物形成的调节。这些目标将是 通过电生理、行为、生物物理和生化技术的组合来解决 在野生型和转基因小鼠身上。在这些实验完成后，我们将确定 糖基化控制阿尔茨海默病tau相关损伤发生的机制 并测试以SUMO2结合为靶点的干预可能会 为他们的治疗提供了有效的治疗方法。

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.