Amyloid oligomers

Abstract

Amyloid diseases are a group of degenerative disorders, such as Alzheimer’s, Huntington’s, Parkinson’s and Prion diseases and amyotrophic lateral sclerosis (ALS). They are characterized by tissue damage caused by toxic aggregates of misfolded proteins called amyloid. To date, more than 20 different proteins or peptides are known to form fibrillar amyloid aggregates associated with human pathologies. Accumulating evidence indicates that amyloid oligomers (which are oligomeric but soluble states of amyloidogenic proteins), rather than insoluble amyloid fibrils, play important roles in various types of amyloid-related degenerative diseases. It has also been suggested that soluble oligomers from different proteins share common structural properties and cellular toxicity mechanisms. This minireview series deals with the structural and biochemical characteristics of various amyloid oligomers and their possible roles in the pathogenesis of the diseases. Recent advances in imaging techniques to understand amyloid oligomer formation are also described. In the first minireview by Sakono & Zako, structures and toxicity mechanisms of soluble amyloid-beta (Aβ) oligomers, which are thought to cause Alzheimer’s disease (AD), are described. At present, many types of Aβ oligomers of different sizes and shapes have been reported, which account for their biological and structural diversity, and for the complexity of AD pathology. Recent studies on Aβ oligomer formation, using single molecule observation techniques, are also described. The single molecule approach overcomes the limitations of resolution and sample heterogeneity, and will be a powerful tool to analyze amyloid oligomer formation and elucidate the formation mechanism at the molecular level. These authors also discuss possible formation mechanisms of extracellular and intracellular Aβ oligomers. In the second minireview by Taguchi & Kawai-Noma, the biological roles of prion oligomers are described. Prions are infectious proteins, by which self-propagating amyloid conformations of proteins are transmitted. Recent advances in techniques capable of investigating the dynamics of protein molecules in living cells, such as single-cell imaging systems, are also described. These techniques provide novel insights into the molecular mechanism of prion propagation and transmission. Using yeast Sup35 as a model prion protein, they suggest that oligomeric species of prion proteins dispersed in the cytoplasm are critical for the transmission of prion phenotypes. The next two minireviews focus on various fluorescent techniques in amyloid aggregation studies. The third minireview, by Kitamura & Kubota, discusses and exemplifies the merits and drawbacks of various spectroscopic analyses, such as fluorescence recovery after photobleaching (FRAP), fluorescence loss in photobleaching (FLIP), fluorescence correlation spectroscopy (FCS) and fluorescence resonance energy transfer (FRET) analysis on the studies on aggregates and soluble oligomers of misfolded proteins. In particular, they focus on the formation of toxic aggregates made up from polyQ-expanded proteins (e.g. involved in Huntington’s disease and in ataxias) and from superoxide dismutase 1 (SOD1) mutants involved in the pathogenesis of ALS. They suggest that protein aggregates of misfolded proteins are dynamic structures that interact with other proteins such as molecular chaperones, and discuss how these oligomers are toxic to cells. In the final minireview, by Lindgren & Hammarström, recent optical spectroscopic studies of amyloid protein misfolding, oligomerization and amyloid fibril growth are reviewed. In particular, detection of oligomeric states and prefibrillar states of amyloidogenic proteins using novel small molecular probes, named ‘luminescent conjugate polymers’ (LCPs), is described. In amyloid research, LCPs that have polythiophene backbones have been used. Optical spectroscopy using these novel molecular probes has shown that the intermediate oligomeric state can be captured and studied in vitro. Molecular probes and optical spectroscopy are now entering a phase that enables in vivo interrogation of the role of oligomers in amyloid diseases. Such techniques used in parallel with in vitro experiments, will probably relate structure to pathogenesis in the near future.