The role of SUMOylation in Tau-mediated pathology

SUMO 化在 Tau 介导的病理学中的作用

基本信息

批准号：
10083243
负责人：
OTTAVIO ARANCIO
金额：
$ 38.6万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083243
关键词：
Acute Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Amyloid beta-Protein Animals Antibodies Atomic Force Microscopy Behavioral Binding Biochemical Biological Assay Biological Models Biophysics Brain Cell Death Cell physiology Cells Cerebrospinal Fluid Circular Dichroism Data Defect Dementia Deposition Development Disease Disease Progression Dorsal Elderly Electrophysiology (science)Etiology Event Exposure to Frontotemporal Dementia Functional disorder Gene Expression Hippocampus (Brain)Human Impaired cognition Impairment Intervention Lasers Link Literature Long-Term Potentiation Lysine Mediating Memory Memory Loss Memory impairment Molecular Mus Neurodegenerative Disorders Nuclear Pathologic Pathology Peptides Phenotype Play Post-Translational Protein Processing Preventive measure Preventive treatment Process Proteins Recombinants Regulation Role Sequence Homology Slice Specificity Structure Sumoylation Pathway Synapses Synaptic plasticity Tauopathies Techniques Testing Toxic effect Transgenic Organisms Transmission Electron Microscopy Ubiquitin Up-Regulation Wild Type Mouse base behavioral impairment effective therapy experimental study genetic approach hTau Mice in vivo light scattering mouse model overexpression paralogous gene peptidomimetics polypeptide protein aggregation protein function protein oligomer segregation synaptic function tau Proteins tau aggregation tau mutation tau phosphorylation therapeutically effective

项目摘要

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.

我们对认知和行为障碍基础的分子机制的不良理解阿尔茨海默氏病的特征是确定阿尔茨海默氏症有效治疗的关键障碍疾病。该项目旨在通过检查sumoylation的能力来解决我们的理解差距翻译后修饰在此中，小肽称为小型泛素样修饰剂（SUMOS）共价连接到靶标底物上的赖氨酸残基，以控制tau的病理作用 - 中央疾病分子病因的成分。 sumoylation是一个可逆的过程，对蛋白质功能，包括定位的调节，许多细胞蛋白的稳定性和活性，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物脊椎动物大脑：SUMO1-3，SUMO2和3共享〜95％的序列同源性（也不是功能上差异化）通常共同称为sumo2/3。有趣的是，sumoylation在阿尔茨海默氏病患者的海马。在初步研究中，我们已经能够连接tau sumoylation 通过SUMO2共轭（而不是SUMO1）保护tau聚集的tau聚集和毒性和毒性。还发现SUMO2降低了聚集的TAU释放。此外，模仿Sumo2共价与TAU结合挽救了寡聚TAU诱导的长期增强损伤（LTP），一种突触可塑性认为是记忆形成的基础，并且在额叶痴呆的小鼠模型中的记忆丧失。在此提案中，我们将通过追求以下特定目的来基于这些观察结果：1）确定是否是否上调SUMO2共轭挽救了Tau引起的突触功能中的缺陷； 2）确定是否上调 SUMO2共轭挽救了小鼠tau引起的记忆缺陷； 3）测试是否的救援效果是否上调SUMO2共轭取决于Tau低聚物形成的调节。这些目标将是通过电生理，行为，生物物理和生化技术的结合来解决在野生型和转基因小鼠中。这些实验完成后，我们将确定 Sumoylation控制着Alzheimer病中与TAU相关障碍的发展的机制并在额叶痴呆症中，并测试靶向sumo2结合的干预措施构成了治疗的有效治疗方法。