The impact of self-replicating proteins on inflammation, autoimmunity and neurodegeneration—An untraveled path.

Abstract The central nervous system (CNS) in neurodegenerative diseases is a battlefield in which microglia fight a highly atypical battle. During the inflammatory process microglia themselves become dysfunctional and even with all the available immune arsenal including cytokine or/and antibody production, the battle is eventually lost. A closer look into the picture will reveal the fact that this is mainly due to the atypical characteristics of the infectious agent. The supramolecular assemblies of misfolded proteins carry unique features not encountered in any of the common pathogens. Through misfolding, proteins undergo conformational changes which make them become immunogenic, neurotoxic and highly infective. The immunogenicity appears to be triggered by the exposure of previously hidden hydrophobic portions in proteins which act as damage-associated molecular patters (DAMPs) for the immune system. The neurotoxicity and infectivity are promoted by the small oligomeric forms of misfolded proteins/peptides. Oligomers adopt conformations such as tubular-like, beta-barrel-like, etc., that penetrate cell membranes through their hydrophobic surfaces, thus destabilizing ionic homeostasis. At the same time, oligomers act as a seed for protein misfolding through a prion/prion-like mechanism. Here, we propose the hypothesis that oligomers have catalytic surfaces and exercise their capacity to infect native proteins through specific characteristics such as hydrophobic, electrostatic and π-π stacking interactions as well as the specific surface area (SSA), surface curvature and surface chemistry of their nanoscale supramolecular assemblies. All these are the key elements for prion/prion-like mechanism of self-replication and disease spreading within the CNS. Thus, understanding the mechanism of prion's templating activity may help us in the prevention and development of novel therapeutic strategies for neurodegenerative diseases. Highlights • The atypical nature of infectious agent as main culprit behind the unorthodox inflammation in neurodegenerative diseases. • The presence of autoantibodies and the molecular mimicry point to an autoimmune component in neurodegenerative diseases. • The revealed hydrophobicity in proteins triggers inflammation, aggregation and perturbs the dynamic of water in the brain. • Oligomers and protofibrils in disease may have catalytic surfaces promoting protein destabilization onto their surfaces. [ABSTRACT FROM AUTHOR]