Studies of diseases associated with pathological irreversible aggregation of proteins have become of special relevance and attracted the attention of researchers throughout the world because of the appearance of a new conceptual model based on the capacity of some proteins to self-assemble by the prion mechanism. Along with direct prion diseases, such as bovine rabies and Creutzfeldt-Jakob disease in humans, a great number of neurodegenerative disorders associated with the formation of aggregates through the prion mechanism are revealed. These disorders include Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, Huntington disease, and mucoviscidosis, some types of diabetes and hereditary cataracts. The listed diseases are caused by transition of a “healthy” protein or peptide molecule from the native conformation to a very stable “pathological” form. In this case, molecules in the “pathological” conformation aggregate specifically, forming amyloid fibrils that can multiply infinitely. An important result of studying the molecular mechanisms of prion diseases and different proteinopathies, associated with the formation of pathological aggregations by the prion mechanism, is the discovery of protein chain regions responsible for their aggregation. The ability to regulate aggregation (fibrillation) of proteins can be the focal tool for the drug development. Herein by the example of 29 RNA-binding proteins with prion-like domains, we demonstrate what role the amino acid repeats in prion-like domains can play. For these proteins, quite different repeats are revealed in the disordered part of the protein chain predicted with bioinformatics methods. Ten proteins of the 29 RNA-binding proteins are involved in the development of some diseases. The prion-like domains of FUS, TAF15, and EWS are critical for the aggregation of proteins associated with human neurodegenerative diseases. Proteins of this family are involved not only in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Huntington disease, spinocerebral ataxy, and dentatorubral pallidoluysian atrophy, but also in the formation of human mixoid liposarcoma. It can be suggested that the presence of a great number of repeats in prion-like domains of RNA-binding proteins can accelerate the formation of a dynamic beta-structure and pathological aggregates, which are crucibles of amyotrophic lateral sclerosis (ALS) pathogenesis.
Part of the book: Update on Amyotrophic Lateral Sclerosis
Aggregation of peptides and proteins into amyloid structure is one of the most intensively studied biological phenomena at the moment. To date, there is no developed theory that would allow one to determine what kind of mechanism presents in the given experiment on the basis of aggregation kinetic data. Debates concerning the mechanism of the amyloid fibrils formation and, in particular, the size of the amyloidogenic nucleus are still going on. We created such a theory on the basis of the kinetics of amyloid aggregates formation. In the presented chapter, theoretical and experimental approaches were employed for studding the process of amyloid formation by different proteins and peptides. The current kinetic models described in this chapter adequately describe the key features of amyloid nucleation and growth.
Part of the book: Exploring New Findings on Amyloidosis