Toxic species in amyloid disorders: Oligomers or mature fibrils

Abstract

Protein aggregation is the hallmark of several neurodegenerative disorders. These protein aggregation (fibrillization) disorders are also known as amyloid disorders. The mechanism of protein aggregation involves conformation switch of the native protein, oligomer formation leading to protofibrils and finally mature fibrils. Mature fibrils have long been considered as the cause of disease pathogenesis; however, recent evidences suggest oligomeric intermediates formed during fibrillization to be toxic. In this review, we have tried to address the ongoing debate for these toxic amyloid species. We did an extensive literature search and collated information from Pubmed (http://www.ncbi.nlm.nih.gov) and Google search using various permutations and combinations of the following keywords: Neurodegeneration, amyloid disorders, protein aggregation, fibrils, oligomers, toxicity, Alzheimer's Disease, Parkinson's Disease. We describe different instances showing the toxicity of mature fibrils as well as oligomers in Alzheimer's Disease and Parkinson's Disease. Distinct structural framework and morphology of amyloid oligomers suggests difference in toxic effect between oligomers and fibrils. We highlight the difference in structure and proposed toxicity pathways for fibrils and oligomers. We also highlight the evidences indicating that intermediary oligomeric species can act as potential diagnostic biomarker. Since the formation of these toxic species follow a common structural switch among various amyloid disorders, the protein aggregation events can be targeted for developing broad-range therapeutics. The therapeutic trials based on the understanding of different protein conformers (monomers, oligomers, protofibrils and fibrils) in amyloid cascade are also described.

Keywords: Amyloid disorders; fibrils; neurodegenerative disorders; oligomers; protein aggregation.

Figure 1

Schematic illustration of protein aggregation in amyloid disorders. Four different aggregation pathways are described here. (a) Native proteins misfold and undergo conformational change to form protofibrils and mature fibrils, (b) Misfolded monomers form off-pathway oligomers which do not end up in fibrils, (c) Mature fibrils undergo shearing or fragmentation to form fibrillar oligomers (originated from fibrils) that again aggregate to form mature fibrils, (d) Mature fibrils act as a template for oligomerization and catalyzes the secondary nucleation reaction by forming diffusible oligomers from the monomers