Mechanism of cell uptake for pathogenic tau seeds

致病性 tau 种子的细胞摄取机制

• 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
• 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' 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

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的神经退行性疾病是一个主要的健康问题。已知的tau蛋白是 在这些疾病中起着关键作用。在疾病状态下，tau从正常的、“健康的”三个- 空间形状是指能够自组装成病理性聚集体的形状。值得注意的是，这些 一旦在脑细胞中形成聚集体，似乎就会离开那个细胞，进入邻近的或相连的 细胞，它们可以作为致病的“模板”，将正常的tau蛋白破坏为异常的tau蛋白。 构象。游离的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。 硫酸盐蛋白多糖(HSPG)，它在细胞内通过附着糖分子进行修饰， 通过添加硫酸盐基团对其本身进行修饰。这些修改发生在 HSPG的合成，并依赖于特定的细胞酶。此前已鉴定出一种名为NDST1的酶 这对于使HSPG能够被适当地修饰以结合tau蛋白非常重要。一旦绑定到 HSPG、tau组件进入细胞，在那里它们产生更多的聚集体。牛磺酸的作用机制 是否能穿过细胞膜尚不清楚。同样未知的是，适用于tau的机制是否 类似于对其他致病蛋白起作用的那些。这项资助将测试NDST亚型的作用 在tau诱导的神经变性的小鼠模型中，看看先前研究所涉及的途径是否可能是 目标是创造治疗阿尔茨海默氏症的新药。此外，这笔拨款将决定tau组件如何 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。