Overview of fibrillar and oligomeric assemblies of amyloidogenic proteins

Abstract

Aberrantly folded proteins are implicated in over 40 human diseases, including neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and Creutzfeldt-Jakob diseases; diseases of particular organs, -including desmin-related cardiomyopathy or type-2 diabetes mellitus; and systemic -diseases, such as senile systemic amyloidosis or light-chain amyloidosis. Although the proteins involved in each disease have unrelated sequences and dissimilar native structures, they all undergo conformational alterations and misfold to form fibrillar polymers characterized by a cross-β structure. Fibrillar assemblies build up progressively into intracellular or extracellular proteinaceous aggregates generating the pathognomonic amyloid-like lesions in vivo. Substantial evidence accumulated in the last decade suggest, that in many amyloid-related diseases, the lesions containing the protein aggregates are the end state of aberrant protein folding whereas the actual culprits causing the disease are soluble, non-fibrillar assemblies preceding the insoluble aggregates. The non-fibrillar protein assemblies are diverse and range from small, low-order oligomers to large assemblies, including spherical, annular, and protofibrillar species. Oligomeric species with different degrees of structural order are believed to mediate various pathogenic mechanisms that may lead to -cellular dysfunction, cytotoxicity, and cell loss, eventuating in disease-specific degeneration. The particular pathologies thus are determined by the afflicted cell types, organs, systems, and the proteins involved. In many cases, the structure-function interrelationships amongst the various protein assemblies described in vitro are still elusive. Moreover, structural and mechanistic studies of amyloid proteins have been challenging due to the dynamic and metastable nature of the non-fibrillar oligomers and the non-crystalline nature of fibrillar protein aggregates. These -factors have confounded the development and potential in vivo application of specific detection tools for non-fibrillar amyloid assemblies. Nevertheless, evidence suggests that non-fibrillar amyloid assemblies may share structural features and possibly common mechanisms of action as assessed in vitro or in situ. Deciphering these intricate structure-function correlations will help in understanding a complex array of pathogenic mechanisms, some of which may be common across different -diseases albeit affecting different cell types or systems. This prefatory chapter aims to give an overview of historical definitions of amyloid along with a general discussion of fibrillar and non-fibrillar amyloid assemblies and their toxicity. The chapter also discusses some methodological challenges, which often are overlooked.