Protein Aggregation of Prion-like Features of Misfolded Ab and Tau

Protein Aggregation & Prion-like Features of Misfolded Ab and Tau

By February 26, 2018 No Comments

Originally Posted on Science Direct | 2 September 2015

scientist studying protein aggregation

Recent findings have shown that several misfolded protein aggregation can transmit disease pathogenesis in a prion-like manner by transferring their conformational properties to normally folded units. However, the extent by which these molecule-to-molecule or cell-to-cell spreading processes reflect the entire prion behavior is now subject of controversy, especially due to the lack of epidemiological data supporting inter-individual transmission of non-prion protein misfolding diseases.

Nevertheless, extensive research has shown that several of the typical characteristics of prions can be observed for AB and tau aggregates when administered in animal models. In this article we review recent studies describing the prion-like features of both proteins, highlighting the similarities with bona fide prions in terms of inter-individual transmission, their strain-like conformational diversity, and the transmission of misfolded protein aggregation by different routes of administration.

Proteins are complex molecules that are critical to the function of cells and tissues in an organism. These macromolecules carry out a multitude of functions, which require the formation of a properly folded state. These physiological processes can be jeopardized in multiple ways when the protein follows alternate folding path-ways.

When a protein becomes misfolded, it loses its ability to perform its biological function and usually gets targeted for degra-dation. Unfortunately, misfolded conformations are prone to form large aggregates that become deposited in cells and tissues and are often resistant to biological clearance. The progressive accu-mulation of misfolded structures is often associated to toxicity and eventually overloads the cell’s protein quality control systems. This misfolded protein burden is then likely to trigger a cascade of events leading to disease (Soto, 2003; Knowles et al., 2014).

Protein misfolding disorders (PMDs) are a diverse class of chronic and progressively degenerative diseases that were first described in the 1850s (Sipe and Cohen, 2000; Soto, 2003; Knowles et al., 2014). Examples of these diseases include Alzheimer’s disease (AD), Parkinson’s disease, type-2 diabetes, non-AD tauopathies, systemic amyloidosis, and transmissible spongiform encephalopathies (TSEs), among others. Although PMDs can affect several organs, the shared target of degeneration in a great number of them is the central nervous system (CNS) (Soto, 2003). In PMDs, diverse proteins aggregate and cause dysfunction in cells and organs leading to clinical signs and ultimately death. Despite their differences in amino acid sequence, all misfolded pro-teins involved in PMDs share similar biochemical and structural features and form large aggregates, often called amyloids, which accumulate in diverse tissues (Sipe and Cohen, 2000; Soto, 2003; Knowles et al., 2014).

In addition to their common end-products, similarities in the process of amyloid formation have been identified for all misfolded proteins as shown in numerous in vitro assays. Several models have been proposed to explain how proteins are incorporated in the misfolded structure; however, the seeding/nucleation model better accounts for the observed data (Jarrett and Lansbury, Jr., 1993).

This model suggests that the aggregation process is initiated by a slow rate step (known as the lag phase) involving the association of soluble/partially misfolded proteins to form small nucleation seeds. Once formed and stabilized, these seeds are thought to cluster and amalgamate to form higher structures at the expenses of the nor-mal protein. This second stage, known as the elongation phase, corresponds to an accelerated and partially irreversible phase of recruitment of proteins into the growing aggregate. Once mature fibrils are formed, oligomers are thought to break off from them to act as new seeds, accelerating the aggregation process (Soto et al., 2006).

Consequently, a shortening in the lag phase can be achieved by feeding the system with previously formed misfolded seeds (Soto et al., 2006). In this sense, exogenously administered seeds can induce the conversion of the soluble proteins in an accelerated way by providing a nucleus for polymerization.


Related Articles on Prions: