Understanding the Effect of Macromolecular Crowding on Protein Misfolding and Aggregation.

Biological molecules evolved and function within cellular environments that are extremely congested by the presence of other macromolecules. A characteristic of the intracellular environment is that it contains the high concentration of macromolecules, the consequences of crowding inside cells. Interior cell spaces are termed crowed rather than concentrated, because no single macromolecular species is present at high concentration; instead, a diverse array of macromolecules collectively occupies a substantial fraction of the cell's volume. In cellular interior, 20-30% volume is occupied by different macromolecules whose global content is approximated to be in a range of 80-400 mg/ml. Crowding is not only applicable to the intracellular environment but also to the extracellular environment of tissues, such as cartilage and blood plasma that contain 80 g/l of protein, a concentration that is sufficiently high to cause substantial macromolecular crowding effects. The effect of macromolecular crowding becomes more prominent during plasmolysis, when there is decrease in hydration of the cells; i.e., loss of water from cells. Ageing cells, e.g. brain and liver cells, lose water content resulting in the increase level of their crowdedness. In this chapter, we propose that with advancing age, the pathogenesis of protein disorder increases as a result of an increase in the effective concentration of amyloidogenic proteins.