About this Research Topic

Background

Protein Misfolding Disorders (PMDs) comprise a heterogeneous group of diseases defined by a process involving the pathological self-assembly of proteins and peptides into a succession of aggregates of increasing molecular size, ultimately depositing in tissues as insoluble amyloid fibrils. Common examples of such diseases include Alzheimer’s and Parkinson’s, and type-2 diabetes mellitus. Thus, pathogenic aggregation intermediates are formed as amyloidogenic protein molecules transition along a misfolding continuum from their monomeric states into highly organized fibrillar aggregates. A consensus is building that the conformations most relevant to toxicity are most likely represented not by the mature fibrils, but by early soluble entities, generally referred to as ‘oligomers’. Targeting oligomeric species by peptide design and small-molecule compounds, either to prevent their formation or convert them into harmless clusters, is therefore of critical importance for the development of effective therapies for these highly debilitating maladies.
Despite extensive research on oligomers in the past 10-15 years, key challenging questions remain to be answered. A major challenge is the extraction and isolation of amyloid oligomers in their native state from human tissues, followed by the determination of their high-resolution structures using biophysical techniques such as cryo-EM and solid-state NMR. Another cutting-edge topic in amyloid research concerns oligomer propagation and cross-seeding, e.g. via exosomes or by prion-like mechanisms, our knowledge of which remains limited. Developing therapies for PMDs based on targeting the highly cytotoxic oligomeric species is still a huge challenge. In this regard, given that direct damage to lipid membranes by amyloid oligomers is commonly observed when addressing PMDs in vitro, targeting oligomer-membrane interactions is a prerequisite to developing effective treatment. In the computational field, we need simulations that allow for longer simulation time scales of aggregation kinetics of intrinsically disordered proteins (or peptides) in bulk solution, and in the presence of lipid membranes. Thus, a combination of in silico, in vitro, in vivo, and pharmacological experiments related to oligomers are needed to address the problems presented in this Research Topic.
The scope of this Research Topic dedicated to amyloid oligomers is to gather a collection of high-quality, freely available, original research and timely review articles which address the major challenges in the field. These include but are not limited to:
• Mechanisms that lead to the formation of protein oligomers
• Quantitative and real-time detection of oligomers along the assembly pathway
• Three-dimensional structures and structural models of amyloid oligomers
• Identifying the major structural determinants of the pathogenicity of oligomers
• Oligomer interaction with biological membranes or membrane mimetics (e.g. lipid-nanodiscs)
• Polymorphism of oligomers
• Detection of oligomers in vivo
• Self-propagation of amyloid oligomers and its role in the trans-cellular spread of the disease
• The role of the proteostasis network in preventing oligomer formation
Both experimental and computational-based research from different disciplines is welcome. It is only thus that we can ensure the prospect of the development of novel therapeutic strategies to treat individuals suffering from PMDs.

Keywords: protein misfolding diseases, peptides, self-assembly, protein aggregation, oligomers, structural biophysics, pathogenicity, amyloid pores, therapy, Alzheimer's disease, Parkinson's disease, type-2 diabetes mellitus, amyotrophic lateral sclerosis

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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