Mechanism of cell uptake for pathogenic tau seeds

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tau蛋白 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- 从三维形状到能够自组装成病理性聚集体的形状。值得注意的是，这些 聚集体一旦在脑细胞中形成，似乎就离开该细胞并进入邻近或连接的细胞。 细胞，在那里它们可以作为致病的“模板”，将正常的tau蛋白破坏成异常的tau蛋白。 构象游离的tau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 硫酸蛋白聚糖（HSPG），其在细胞中通过糖分子的附着而被修饰， 其本身通过加入硫酸根基团而被改性。这些修改发生在 HSPG的合成，并依赖于特定的细胞酶。一种酶，NDST 1，以前被确定为 这对于使HSPG能够被适当修饰以结合tau蛋白是非常重要的。一旦结合 HSPGs和tau蛋白聚集体进入细胞，在那里它们产生更多的聚集体。tau蛋白的作用机制 能不能穿过细胞膜是未知的。也不知道适用于tau的机制是否 与其他致病蛋白的功能相似。这项资助将测试NDST亚型的作用 在tau蛋白诱导的神经退行性变的小鼠模型中，观察先前研究涉及的途径是否可能 旨在研发治疗阿尔茨海默氏症的新药此外，该赠款将决定如何陶大会可以 以及适用于tau蛋白的机制是否也适用于其他致病性疾病 proteins.

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.