Cellular factors implicated in amyloid fibril homeostasis

能够形成淀粉样蛋白结构的蛋白质和蛋白质片段的数量很大(&gt；50)，相关退行性疾病的数量也很多。近年来，淀粉样蛋白稳态的关键方面已成为人们关注的焦点，但尚未完全了解。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，不仅是传染性的普恩蛋白，而且由Abeta和tau组成的淀粉样蛋白也能够在细胞间传播，这凸显了对这一领域进行基础机制研究的必要性和重要性。这项建议的总体目标是以已建立的tau蛋白和Abeta多肽为模型，对淀粉样蛋白稳态的关键方面进行更深入的了解。在此背景下，一种新的交联因子赖氨酰氧化酶2在淀粉样蛋白动态平衡中的意义将被解决。此外，丝氨酸蛋白酶HTRA1的功能和调节将通过重点研究赖氨酰氧化酶2和最近发现的HTRA1-Calpain 2复合体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。

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.