Misfolded protein aggregates: mechanisms, structures and potential for disease transmission

Abstract

Some of the most prevalent human degenerative diseases appear as a result of the misfolding and aggregation of proteins. Compelling evidence suggest that misfolded protein aggregates play an important role in cell dysfunction and tissue damage, leading to the disease. Prion protein (Prion diseases), amyloid-beta (Alzheimer's disease), alpha-synuclein (Parkinson's disease), Huntingtin (Huntington's disease), serum amyloid A (AA amyloidosis) and islet amyloid polypeptide (type 2 diabetes) are some of the proteins that trigger disease when they get misfolded. The recent understanding of the crucial role of misfolded proteins as well as the structural requirements and mechanism of protein misfolding have raised the possibility that these diseases may be transmissible by self-propagation of the protein misfolding process in a similar way as the infamous prions transmit prion diseases. Future research in this field should aim to clarify this possibility and translate the knowledge of the basic disease mechanisms into development of novel strategies for early diagnosis and efficient treatment.

Figure 1. Transmission of Protein Misfolding between molecules, cells and individuals

Prion-like transmission of protein misfolding may operate at various levels, including molecule-to-molecule, cell-to-cell and host-to-host. Propagation of the pathological conformational changes and downstream effects to cells, tissues and the entire individual appears to be a universal property of misfolded protein aggregates.