Many biologically active proteins act as specific oligomers. Structural proteins assemble into sophisticated supramolecular complexes that play various roles in a cell’s life. The formation of such functional oligomers and supramolecular complexes is tightly controlled and regulated. On the other hand, protein misfolding and subsequent uncontrolled (or unwanted) self-aggregation are known pathogens, which are now considered as potential driving forces for the development of a number of human diseases [1–6]. In fact, pathogenic proteinaceous deposits are at the heart of several so-called conformational diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), diffuse Lewy bodies disease, Lewy bodies variant of AD, dementia with Lewy bodies, multiple system atrophy, Hallervorden–Spatz disease, light chain-associated amyloidosis, light chain deposition disease, amyloidosis associated with hemodialysis, Huntington disease, spinal and bulbar muscular atrophy, spinocerebellar ataxia, neuronal intranuclear inclusion disease, Creutzfeld–Jacob disease, Gerstmann–Straussler–Schneiker syndrome, fatal familial insomnia and Kuru. These, and many other diseases, originate from the conversion of soluble and harmless protein into stable, ordered, filamentous protein aggregates, commonly referred to as amyloid fibrils, which can accumulate in a variety of organs and tissues. At least 21 different proteins have been recognized as causative agents of these conformational diseases . Protein aggregation in general, and amyloid fibrillation in particular, is a highly selective molecular self-assembly process. As a result, proteinaceous deposits found in different diseases predominantly contain aggregated forms of a specific causative protein, unique for a given disorder. This raises the question of what drives the transformation of a biologically active soluble protein into a pathogenic misfolded conformation with high self-aggregation potential. Some of the possible mechanisms include : an intrinsic propensity of some proteins to assume a pathological conformation, which becomes evident either with aging (e.g. normal α-synuclein in sporadic forms of PD and other synucleinopathies , and normal transthyretin in patients with senile systemic amyloidosis ) or as a result of unnaturally and persistently high cellular or plasma concentrations (e.g. triplication of a normal α-synuclein gene in some familial forms of PD [11–13], accumulation of β2-microglobulin in patients undergoing long-term hemodialysis , locally high insulin concentrations at the injection sites because of the slow release of insulin from the injection site ); the point amino acid mutations in causative proteins (e.g. familial forms of AD and PD, various hereditary amyloidoses); the genetic expansion of a CAG repeat in ORFs of genes encoding corresponding proteins (e.g. Huntington disease, spinal and bulbar muscular atrophy and spinocerebellar ataxia); the abnormal post-translational modifications of the causative proteins (e.g. hyperphosphorylation of tau protein in AD); the proteolytic cleavage of the precursor protein (e.g. β-amyloid precursor protein in AD); the exposure to some environmental agents that can bring about pathogenic conformational changes in the causative proteins (e.g. structural changes induced by pesticides, herbicides or heavy metals in PD-related protein α-synuclein, structural consequences of oxidative damage, etc.). These and other mechanisms can act independently, additively, or even synergistically.
The accumulation of protein deposits is commonly associated with severe cellular degeneration at the deposition places, the precise mechanisms of which remain elusive . It is not clear whether amyloid fibrils trigger the cellular degeneration or simply represent highly visible side products of the cellular disruption process. However, it has been established that protein misfolding/aggregation and cellular degeneration are coupled. As it was nicely summarized in a recent review , there are several potential mechanisms of such cytotoxicity originating from protein deposition. These include: the disruption of the tissue architecture and functions promoted by the invasion of the extracellular space of organ by amyloids [8,18]; the destabilization of intracellular and extracellular membranes by oligomers, the formation of which may precede or coincide with the appearance of amyloid fibrils [19,20]; the apoptotic cell death and receptor-mediated toxicity triggered by the oligomer interaction with various neuronal receptors ; the oligomer-mediated impairment of the presynaptic P/Q-type calcium currents ; the impaired maturation of autophagosomes to lysosomes mediated by the oligomer accumulation ; the dysfunction of autophagy, a lysosomal pathway for degrading organelles and proteins ; the oxidative damage-induced disruption of the cell viability promoted by the incorporation of redox metals into amyloid fibrils and the subsequent generation of reactive oxygen species [25–29]; the general disorganization of cellular protein homeostasis associated with the exhaustion of the cell defense mechanisms, such as a chaperone system [30,31]; proteasome inhibition ; the loss of crucial protein function(s) and/or the gain of toxic function(s).
All this explains why the problems of misfolding, aggregation and amyloid fibril formation have gained considerable attention from researchers. An intriguing recent development in this field is the immerging recognition of the multiple unique roles that soluble amyloid oligomers (which are oligomeric but soluble states of amyloidogenic proteins) play both as crucial precursors of amyloid fibrils and as independent toxic agents. Despite these facts, information on the structural properties of soluble oligomers and the mechanisms of their formation and interconversion is sparse, and the understanding of the molecular mechanisms of their toxicity remains mostly elusive. This review provides an overview of some topics related to these issues.