Overview of Fibrillar and Oligomeric Assemblies of Amyloidogenic Proteins

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