How can changes in protein isomer concentration trigger protein aggregation diseases?

Conner Sandefur (November 6, 2010)

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Conformational diseases result from the failure of a specific protein to fold into its correct functional state. The misfolded proteins can lead to the toxic aggregation of proteins. In some cases, misfolded proteins interact with bystanders proteins (unfolded and native folded proteins), eliciting a misfolded phenotype. These bystander polypeptides would follow their normal physiological pathways in absence of misfolded proteins. In some conformational diseases, evidence suggests that bystander protein disappearance occurs through direct or indirect interaction with misfolded proteins, resulting in a transformation into aggregate-prone misfolded protein. Protein aggregation in conformational diseases often displays a threshold phenomenon characterized by a sudden shift between nontoxic and toxic levels of protein aggregates. We propose a general mechanism of bystander and misfolded protein interaction to investigate how the threshold phenomenon in protein aggregation is triggered in conformational diseases. Using a continuous flow reactor model of the endoplasmic reticulum, we derived the conditions necessary to produce threshold phenomena. Our results indicate that slight changes in the ratio of misfolded to bystander basal protein concentrations can trigger the threshold phenomena in protein aggregation. Our model proposes a general mechanism for the loss of function observed in certain conformational diseases. We also identify the conditions necessary to trigger the observed threshold phenomena in protein aggregation. Understanding the conditions necessary for the aggregation threshold phenomena is an important step towards developing therapeutic strategies targeting the modulation of conformational diseases.