Cellular factors implicated in amyloid fibril homeostasis

能够形成淀粉样结构的蛋白质和蛋白质片段的数量很大（>50），相关退行性疾病的数量也很大。近年来，淀粉样蛋白稳态的关键方面已经成为焦点，但尚未完全理解。普遍相关的问题包括有助于淀粉样蛋白形成的细胞因子以及与β-淀粉样蛋白的解离和降解有关的细胞因子。此外，它已经变得很清楚，不仅是传染性朊病毒，而且淀粉样蛋白组成的Abeta和tau是能够细胞间的传播突出的需要和重要性的基本机制研究到这一领域。本提案的总体目标是获得更深入的了解淀粉样蛋白稳态的关键方面，使用已建立的tau蛋白和Abeta肽作为模型。在这种情况下，一种新的交联因子，赖氨酰氧化酶2，在淀粉样蛋白稳态的影响将得到解决。此外，将通过重点关注赖氨酰氧化酶2和最近发现的HTRA 1-Calpain 2复合物如何影响这种蛋白质质量控制蛋白酶在淀粉样蛋白稳态中的保护作用来研究丝氨酸蛋白酶HTRA 1的功能和调节。

The number of proteins and protein fragments capable of forming amyloid structures is large (>50) as is the number of related degenerative diseases. In recent years, critical aspects of amyloid homeostasis have come into focus but are not yet fully understood. Issues of general relevance include cellular factors contributing to amyloid formation and such that are implicated in dissociation and degradation of beta-amyloids. Moreover, it has become clear that not only infectious prions but also amyloids composed of Abeta and tau are capable of intercellular spreading highlighting the need and importance of basic mechanistic research into this area.The general objective of this proposal is to obtain deeper insights into critical aspects of amyloid homeostasis using the established tau protein and Abeta peptide as models. In this context, the implications of a novel crosslinking factor, lysyl oxidase 2, in amyloid homeostasis will be addressed. In addition, the functions and regulation of the serine protease HTRA1 will be investigated by focusing on how lysyl oxidase 2 and a recently discovered HTRA1-Calpain2 complex affect the protective roles of this protein quality control protease in amyloid homeostasis.