Mechanism of cell uptake for pathogenic tau seeds

致病性 tau 种子的细胞摄取机制

基本信息

批准号：
10375102
负责人：
MARC I DIAMOND
金额：
$ 68.01万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10375102
关键词：
3-Dimensional Alzheimer&apos s Disease Amyloid Amyloid Proteins Animal Model Bilateral Binding Biosensor Brain region CRISPR screen Cations Cell Line Cell membrane Cell model Cell surface Cells Clinical Cultured Cells Cytoplasm Development Diagnostic Disease Disease Progression Endocytosis Enzymes Fluorescence Resonance Energy Transfer Genes Grant HIV Health Heparan Sulfate Proteoglycan Heparitin Sulfate Human Image Immunotherapy Induced pluripotent stem cell derived neurons Injections Lead Lipofectamine Mediating Membrane Methods Modeling Modification Molecular Conformation Mus Nerve Degeneration Neurodegenerative Disorders Neurons Pathologic Pathology Pathway interactions Peptides Plasma Play Process Propidium Diiodide Protein Isoforms Proteins Publishing Role Seeds Shapes Specificity Structure Sulfate System Tauopathies Testing Therapeutic Transfection Validation Vesicle Work alpha synuclein brain cell cell immortalization endosome membrane extracellular feasibility testing fluorophore frontal lobe in vivo in vivo evaluation knock-down mouse model novel novel therapeutic intervention novel therapeutics prevent protein TDP-43 selective expression sugar synuclein tau Proteins tau aggregation tau mutation therapeutic development therapy development trafficking transmission process uptake vector whole genome

项目摘要

Alzheimer’s and related neurodegenerative diseases are a major health problem. The tau protein is known to play a critical role in these disorders. In the disease state tau transitions from a normal, “healthy” three- dimensional shape to one that is capable of self-assembling into pathological aggregates. Remarkably, these aggregates, once formed in a brain cell, appear to exit that cell and gain entry into neighboring or connected cells, where they can serve as disease-causing “templates” to corrupt normal tau protein to an abnormal conformation. Free tau aggregates can bind the cell surface by interacting with specific proteins called heparan sulfate proteoglycans (HSPGs), which are modified in the cell through the attachment of sugar molecules, which themselves are modified by the addition of sulfate groups. These modifications occur during the synthesis of HSPGs, and depend on specific cellular enzymes. One enzyme, NDST1, was previously identified as being very important for enabling HSPGs to be properly modified so as to bind tau protein. Once bound to HSPGs, tau assemblies get into the cell, where they create more aggregates. The mechanisms by which tau can cross the cell membrane are unknown. It is also unknown whether the mechanisms that apply to tau are similar to those that function for other disease-causing proteins. This grant will test the role of NDST isoforms in a mouse model of tau-induced neurodegeneration to see if the pathway implicated by prior studies might be targeted to create new drugs for Alzheimer’s. Additionally, the grant will determine how tau assemblies can cross the cell membrane, and whether mechanisms that apply to tau also apply to other disease-causing proteins.

阿尔茨海默氏症和相关神经退行性疾病是一个主要的健康问题。已知tau蛋白在这些疾病中起关键作用。在疾病状态下，tau从正常的“健康”三个尺寸形状到能够自组装成病理聚集体的形状。值得注意的是，这些骨料一旦形成在脑细胞中，似乎将退出该细胞并进入相邻或连接细胞，它们可以用作引起疾病的“模板”，以损坏正常tau蛋白的异常构象。游离tau聚集体可以通过与称为肝素的特定蛋白质相互作用来结合细胞表面硫酸盐蛋白聚糖（HSPG），通过糖分子的附着在细胞中修饰，它本身是通过添加硫酸基团修改的。这些修改发生在 HSPG的合成，并取决于特定的细胞酶。先前已经鉴定出一种酶NDST1 对于使HSPG进行适当修改以结合tau蛋白非常重要。一旦绑定到 hspgs，tau组件进入单元格，在那里它们创建更多的聚集体。 tau的机制可以越过细胞膜是未知的。也未知适用于tau的机制是类似于那些起作用其他引起疾病蛋白的功能。该赠款将测试NDST同工型的作用在tau诱导的神经变性的小鼠模型中，查看先前研究是否实现了该途径目标是为阿尔茨海默氏症创建新药。此外，赠款将确定tau组件如何越过细胞膜，以及适用于TAU的机制是否也适用于其他引起疾病的机制蛋白质。