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.

众所周知，阿尔茨海默氏症和相关的神经退行性疾病是一个主要的健康问题。在疾病状态下，tau蛋白从正常、“健康”的三态转变中发挥着关键作用。值得注意的是，这些形状能够自我组装成病理性的聚合体。聚集体一旦在脑细胞中形成，就会离开该细胞并进入邻近或相连的细胞细胞，它们可以作为致病的“模板”，将正常的 tau 蛋白破坏成异常的游离的 tau 蛋白聚集体可以通过与称为乙酰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进行修饰，它们本身通过添加硫酸基团进行改性，这些改性发生在 HSPG 的合成依赖于一种特定的细胞酶，NDST1，之前已被鉴定出。对于 HSPG 进行适当修饰以便与 tau 蛋白结合非常重要。 HSPG、tau 蛋白组装体进入细胞，在细胞中产生更多 tau 蛋白聚集体的机制。 tau 蛋白能否穿过细胞膜尚不清楚。与其他致病蛋白的功能类似，这笔资助将测试 NDST 亚型的作用。在 tau 诱导的神经变性小鼠模型中，看看先前研究所涉及的通路是否可能是此外，这笔资金还将确定 tau 蛋白组装的用途。穿过细胞膜，以及适用于 tau 的机制是否也适用于其他致病因素蛋白质。