Alpha-synuclein (AS) is the major constituent of Lewy bodies, a pathological signature of Parkinson’s disease (PD). Amyloid-like deposits of AS are generated by toxic pre-fibrillar species of the protein which are now considered to be a major cause of cell death in PD. The mechanisms by which oxidative stress is linked to AS aggregation are not yet known and are a subject of intense research in the field. The most appealing hypothesis is the one of oxidation-mediated oligomerization of AS, causing the formation of highly toxic early amyloidogenic species. Such intermediates appear to be scarcely populated, likely involving important structural rearrangements, what makes them ideal targets for drug intervention. The focus of this research proposal is to characterise the structure and thermodynamics of early AS amyloidogenic species, both the molten globule-like conformation of monomeric AS, reported to be key intermediate in fibril formation, and small early soluble oligomers populated in different conditions. The study of the early stages of fibrillogenesis requires the development and application of new methods. We propose tackling this challenge in a novel way, through exciting multidisciplinary research by scaling up the NMR techniques combined with methods of molecular dynamics simulations, together with the use of the more advanced single-molecule fluorescence techniques. In addition, the impact of metal-catalized oxidation in the structure of monomeric and oligomeric AS by means of low and high resolution structural techniques will be evaluated, shedding light into the role of oxidative damage as an effector in protein aggregation. The information obtained will be paramount in order to validate the use of pharmacological chaperones of AS as new therapeutic agents to treat PD.
Field of science
- /medical and health sciences/basic medicine/neurology/parkinson
- /natural sciences/biological sciences/biochemistry/biomolecules/proteins
Call for proposal
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