Cellular factors implicated in amyloid fibril homeostasis

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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.