Amyloid fibrils: The eighth wonder of the world in protein folding and aggregation

摘要

Protein folding, misfolding, and aggregation are among the central topics of molecular biology in the postgenome era. Increasing evidence indicates that protein aggregation plays a vital role in a variety of biological processes. Specifically, fibrillar aggregates, i.e., filamentous assemblies of peptides and proteins that possess a common cross-beta sheet structure, have been found in a wide range of organisms, from bacteria to mammals, and have been shown to possess different physiological functions. However, the extensive research on fibrillar aggregates has primarily been driven by the fact that some of these aggregates, known as amyloid fibrils, are found as deposits in the tissues and organs of patients diagnosed with various amyloid-associated diseases such as Alzheimer's disease, Parkinson's disease, Hunting-ton's disease, prion disease, type-2 diabetes, etc. (1). These maladies can be sporadic, inherited, or even infectious, and misfolded protein aggregates are often considered biomedical markers of these diseases. Despite great interest, a full understanding of the causes of these diseases and the roles of protein oligomers and fibrils has not yet been achieved. According to one hypothesis, an abnormally high local protein concentration in multivesicular bodies results in protein aggregation. These prefibrillar aggregates cause cell death and the release of toxic species into the extracellular space. In this regard, the formation of mature fibrils is considered a defense mechanism, which nature uses to clear these toxic oligomers from the cell media. Therefore, prefibrillar oligomers rather than mature fibrils are thought to be responsible for the progression of neurodegenerative diseases.