Amyloid fibrils

Amyloidoses constitute a group of diverse diseases in which extracellular insoluble material is deposited either systemically or in specific organs, which leads to the destruction of surrounding cells. The amyloid diseases encompass some of today’s most devastating maladies, both in terms of number of people affected and in the extent of human suffering, including Alzheimer’s disease, spongiform encephalopathies and type II diabetes mellitus. The term amyloid was originally introduced to describe the tissue deposits seen in histological sections as it was thought that they were composed of starch-like material. Today it is known that protein constitutes the main component of amyloid deposits, although other constituents are found as well. In order to form these deposits, the proteins involved must convert from their native (folded or unfolded) states and aggregate into insoluble fibrils with cross b-sheet structure. The fibrils themselves and ⁄or oligomers formed on the pathway to fibril formation are thought to be cytotoxic, and thereby directly responsible for disease initiation and progression. For each of the amyloid diseases, one specific protein or peptide forms the fibrils, for example the amyloid b-peptide (Ab) in Alzheimer’s disease, the prion protein (PrP) in spongiform encephalopathies and the islet amyloid polypeptide (IAPP) in type II diabetes. Our knowledge about amyloid diseases and the constituent proteins at a molecular level has expanded significantly during the last few years and the minireviews in this issue of FEBS Journal summarize the progress made from four different angles. The contribution by Per Westermark describes the pathology of the amyloidoses, defines the 25 known amyloidogenic proteins in a systematic manner and gives an outlook on future lines of research. Particularly interesting, and potentially horrifying, is the possibility of lateral spread of amyloidoses, as a result of the inherent self-propagating nature of fibril growth and the potential for cross-seeding between different amyloidogenic proteins. In the second review, Sumner Makin & Louise Serpell discuss current knowledge on the molecular structures of amyloid fibrils. Recent progress of these authors and others has resulted in the determination of high-resolution structures of amyloid fibrils. The details of these structures are described, highlighting, among other things, the impressive complementarity between the strands that build up the cross b-sheet polymers, and the ways in which this knowledge impacts our understanding of disease progression are discussed. In the third review, Thomas Jahn & Sheena Radford describe what has been learnt from biophysical studies of protein folding and unfolding as regards the driving forces of amyloid fibril formation. In the light of this they discuss how different perturbations of a biological system could lead to the switch from a kinetically favoured native state towards the globally most stable structure, the amyloid fibril. In the final contribution in the series, Ehud Gazit summarizes recent work on mechanistic aspects of fibril formation, in particular how the amino acid sequence determines the propensity to fibrillation and how short peptides can be used to study this aspect. Gazit also discusses how a detailed understanding of fibril formation and structure can be used to design inhibitors. , The amyloidoses are fatal diseases and the number of affected people is expected to increase significantly in the coming decades, but no curative treatment is yet available for any of these conditions. The apparent close connection among amyloid disease, fibril formation and protein folding and misfolding, makes it likely that continued intense interest in these topics will eventually generate mechanism-based inhibitors that can be used to combat these devastating diseases.