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：
10540308
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540308
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 Induction 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 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 Persons Phenotype Play Post-Translational Protein Processing Preventive measure Preventive treatment Process Proteins Recombinants Regulation Role SUMO1 gene Sequence Homology Slice Specificity Sumoylation Pathway Synapses Synaptic plasticity Tauopathies Techniques Testing Toxic effect Transfection Transgenic Mice Transgenic Organisms Transmission Electron Microscopy Ubiquitin Up-Regulation Wild Type Mouse 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-1 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背后的分子机制了解甚少阿尔茨海默病的特征是识别阿尔茨海默病有效治疗方法的关键障碍该项目旨在通过检查 SUMOylation 的能力来解决我们理解上的这一差距。翻译后修饰过程中产生称为小泛素样修饰剂 (SUMO) 的小肽共价连接到目标底物上的赖氨酸残基，以控制 tau 的病理作用——tau 是一个中心 SUMO化是该疾病分子病因学的一个组成部分，是一个可逆过程，对疾病有多种影响。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存在三个已知的 SUMO 旁系同源物。脊椎动物大脑：SUMO1-3，SUMO2 和 3 具有约 95% 的序列同源性（并且在功能上没有微分）通常统称为 SUMO2/3。在初步研究中，我们已经能够将 tau 蛋白 SUMO 化联系起来。通过 SUMO2 缀合（但不是 SUMO1）防止 tau 聚集，从而降低 tau 聚集和毒性此外，SUMO2 还被发现可以减少 tau 蛋白的聚集释放，模仿 SUMO2 共价键。与 tau 结合可挽救寡聚 tau 诱导的长时程增强 (LTP) 损伤，LTP 是一种突触可塑性被认为是额颞叶痴呆小鼠模型记忆形成和记忆丧失的基础。在本提案中，我们将通过追求以下具体目标来建立这些观察结果：1）确定是否上调 SUMO2 结合可挽救 tau 诱导的突触功能缺陷 2) 确定是否上调； SUMO2缀合可挽救tau诱导的小鼠记忆缺陷；3）测试是否有挽救作用；上调 SUMO2 缀合取决于 tau 寡聚体形成的调节。通过电生理学、行为学、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，完成这些实验后，我们将鉴定出。 SUMOylation 控制阿尔茨海默病中 tau 相关损伤发展的机制以及额颞叶痴呆，并测试针对 SUMO2 结合的干预措施的可能性构成了对其治疗的有效治疗方法。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nitric oxide/cGMP/CREB pathway and amyloid-beta crosstalk: From physiology to Alzheimer's disease.

一氧化氮/cGMP/CREB 途径和淀粉样蛋白-β 串扰：从生理学到阿尔茨海默病。

DOI：
10.1016/j.freeradbiomed.2022.11.022
发表时间：
2022-11-01
期刊：
Free radical biology & medicine
影响因子：
7.4
作者：
Maria Rosaria Tropea;Walter Gulisano;Valeria Vacanti;O. Arancio;D. Puzzo;A. Palmeri
通讯作者：
A. Palmeri

Extracellular tau oligomers affect extracellular glutamate handling by astrocytes through downregulation of GLT-1 expression and impairment of NKA1A2 function.

细胞外 tau 寡聚体通过下调 GLT-1 表达和损害 NKA1A2 功能来影响星形胶质细胞对细胞外谷氨酸的处理。

DOI：
发表时间：
2022-08
期刊：
影响因子：
5
作者：
Li Puma, Domenica Donatella;Ripoli, Cristian;Puliatti, Giulia;Pastore, Francesco;Lazzarino, Giacomo;Tavazzi, Barbara;Arancio, Ottavio;Piacentini, Roberto;Grassi, Claudio
通讯作者：
Grassi, Claudio

Development of novel phosphodiesterase 5 inhibitors for the therapy of Alzheimer's disease.

开发用于治疗阿尔茨海默病的新型磷酸二酯酶 5 抑制剂。

DOI：
发表时间：
2020
期刊：
影响因子：
5.8
作者：
Zuccarello, Elisa;Acquarone, Erica;Calcagno, Elisa;Argyrousi, Elentina K;Deng, Shi;Landry, Donald W;Arancio, Ottavio;Fiorito, Jole
通讯作者：
Fiorito, Jole

Optimizing metabolic stability of phosphodiesterase 5 inhibitors: Discovery of a potent N-(pyridin-3-ylmethyl)quinoline derivative targeting synaptic plasticity.

优化磷酸二酯酶 5 抑制剂的代谢稳定性：发现一种针对突触可塑性的有效 N-(吡啶-3-基甲基)喹啉衍生物。

DOI：
发表时间：
2023-08-15
期刊：
影响因子：
2.7
作者：
Zuccarello, Elisa;Zhang, Hong;Acquarone, Erica;Pham, Dang;Staniszewski, Anna;Deng, Shi;Landry, Donald W;Arancio, Ottavio;Fiorito, Jole
通讯作者：
Fiorito, Jole

What Does the APP Family Do in the Brain?

APP家族在大脑中起什么作用？