**Influence of Repeats in the Protein Chain on its Aggregation Capacity for ALS-Associated Proteins**

Oxana V. Galzitskaya

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/63104

#### **Abstract**

Studies of diseases associated with pathological irreversible aggregation of proteins have become of special relevance and attracted the attention of researchers through‐ out 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 mucovis‐ cidosis, 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 aggrega‐ tions 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 prionlike 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 aggrega‐ tion 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 pallido‐ luysian 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 RNAbinding proteins can accelerate the formation of a dynamic beta-structure and

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pathological aggregates, which are crucibles of amyotrophic lateral sclerosis (ALS) pathogenesis.

**Keywords:** disordered regions, repeats, motifs of low complexity, Alzheimer's dis‐ ease, amyotrophic lateral sclerosis (ALS)

#### **1. Introduction**

Misfolded proteins leading to formation of protein aggregations are a reason for many diseases. There is no definite answer to the question what causes death of cells where such aggregations have been found: is this the cell defence mechanism or plain death? In a normal state, cells that accumulate such aggregations are usually programmed to death or apopto‐ sis. Cell fragments subjected to apoptosis are removed by phagocytic cells. However, aggregations like amyloid fibrils are known to be resistant to the action of different proteas‐ es [1] that can impede the effective termination of efferocytosis and, as a result, accumulate in tissues. In any case, there is undoubtedly close association of the formation of aggregations and the development of many fatal diseases. There are several models describing the process of fibril formation. For example, in order to begin aggregation, proteins should be prelimi‐ narily unfolded or partially folded [2]. As known, the generation of fibrils is facilitated by denaturing conditions. At the same time, aggregation of peptides and proteins involved in pathogenesis of such types of amyloidosis as type II diabetes, Alzheimer's, and Parkinson's diseases does not necessitate preliminary unfolding of a protein molecule. But these data sooner support the general rule, because under physiological conditions most of these proteins have no definite structure, i.e., are natively unstructured [3]. However, most natively unfolded protein in vivo does not aggregate [4]. Moreover, unstructured proteins are resistant to denaturing conditions, i.e., to the factors bringing about stress, and, in the first place, high temperatures [5]. It was demonstrated that the absence of structure does not correlate with the aggregation capacity [6]. Therefore to avoid spontaneous self-assembly of a protein mole‐ cule, the evolutionary selection has led to an increased content of such amino acids as proline and glycine that inhibit protein aggregation [7] and to an increased content of charged amino acids [8]. On the contrary, due to a large number of amyloidogenic regions, globular pro‐ teins have developed capacity to avoid aggregation because of rapid folding into a globular structure. This shows that protein unfolding is necessary but not sufficient for activation of amyloid fibrils. It is most likely that there should be special motifs of amino acid sequences exposed to the solvent, which are more liable to aggregation than other regions of the amino acid sequences. Experimental data corroborate the hypothesis that there are small regions of a protein molecule responsible to the amyloidogenic behavior [9–11].
