CONICET | Buscador de Institutos y Recursos Humanos

Parkinson´s disease (PD) is a debilitating and incurable neurodegenerative disease that affects more than 1% of the population above 60 years-old. The combination of genetic predispositions and external factors, such as compounds that promote oxidative stress, promote the gain of toxic function of the protein alpha-Synuclein(aSyn), even in the absence of genetic mutations in its coding gene, SNCA, thatends up forming insoluble amyloid aggregates known as Lewy bodies. The identity of the toxic species responsible for PD remains elusive. In this context, we propose that post-translational modifications (PTMs), as a well-known source of variability of proteins´ structure, function, and localization, may be responsible of triggering the pathological role of aSyn in neurons.We have generated a series of oxidative modifications on recombinant aSyn with a photo-tunable method based on Ru complexes photosensitizer that promote selectively Tyr-residues oxidation through a radical mechanism. This method has been adapted to generate both covalent oligomers and nitrated monomers of a Syn. On the other hand, we have also generated cathecolamine-modified and acetylated aSyn. We characterized these proteins variants by mass spectrometry to confirm PTMs positions and exposure of Tyr residues under different conformational states. Biochemical characterization is underway to analyze the effect of each PTM on amyloid aggregation, membrane binding and cytotoxicity i nneuron-like cell cultures to evaluate their putative increase in toxicity.Finally, the systematic and reproducible production of modified aSyn is being used to generate tools and methods, such as Nanobodies (VHHs) or MRM-MS, that could quantitate specific PTMs in circulating aSyn as early biomarkers of PD pathology.