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.

Correlation between Protective Immunity to α-Synuclein Aggregates, Oxidative Stress and Inflammation

“…In normal physiological conditions, α-synuclein exists intrinsically as an unfolded protein, but during altered conditions in vitro and in vivo, it may self-assemble to form ordered fibrillar aggregates [35] characterized by a cross-β-sheet structure similar to the aggregates found in Lewy bodies [36]. It is interesting that the initial phase of the α-synuclein aggregation process is thought to involve the formation of oligomeric species which possess a much higher degree of cytotoxicity than the mature fibrils into which they develop [1,4,37]. How α-synuclein species cause neurodegeneration is currently unknown, but increased expression of this protein is associated with elevated susceptibility of cells to oxidative stress, DA toxicity and apoptosis [38].…”

Nanotechnology for neurodegenerative disorders

“…In the aim to set up techniques for in vitro diagnosis of PD, An et al [30] utilized Au-doped TiO 2 nanotube (NT) arrays to design a high sensitivity photoelectrochemical immunosensor for ␣-synuclein detection, while Yu and Lyubchenko [31] developed a novel tool based on nanomanipulation of a single molecule of alpha-synuclein to characterize its misfolding and self-assembly by AFM. Previously, Baron et al [32] developed an in vitro quantitative assay for neurotransmitters involved in PD pathology, exploiting plasmon absorbance and Au NP.…”

A comparative study of four different temperatures on structural character of α-syn12 peptide in solution

“…parkinson's disease is characterized by the deposition of aggregated fibrillar α-synuclein in Lewy bodies within brain [1][2][3][4][5].…”