Early Stages for Parkinson’s Development: α-Synuclein Misfolding and Aggregation

Abstract

Misfolding and aggregation of proteins are common threads linking a number of important human health problems, including various neurodegenerative disorders such as Parkinson's disease in particular. The first and perhaps most important elements in most neurodegenerative processes are misfolding and aggregation of specific proteins. Despite the crucial importance of protein misfolding and abnormal interactions, very little is currently known about the molecular mechanism underlying these processes. Factors that lead to protein misfolding and aggregation in vitro are poorly understood, in addition to the complexities involved in the formation of protein nanoparticles with different morphologies (e.g. nanopores and other species) in vivo. A clear understanding of the molecular mechanisms of misfolding and aggregation will facilitate rational approaches to prevent protein misfolding mediated pathologies. To accomplish this goal and to elucidate the mechanism of protein misfolding, we developed a novel nanotechnology tool capable of detecting protein misfolding. We applied single molecule probing technique to characterize misfolding and self-assembly of alpha-synuclein dimers, which is the very first step of the aggregation process. Using AFM force spectroscopy approach, we were able to detect protein misfolding via enhanced interprotein interaction. Moreover, such an important characteristic as the lifetime of dimers formed by misfolded alpha-synuclein was measured. These data suggest that compared to highly dynamic monomeric forms, alpha-synuclein dimers are practically static and thus can play a role of aggregation nuclei for the formation of aggregates. Importantly, two different dissociation channels were detected suggesting that aggregation process can follow different pathways. The application of these findings for understanding of the aggregation phenomenon and the development of the disease is discussed.