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. It is included in a group of pathologies known as Synucleinopathies, whose main common feature is the cytosolic presence of amyloid aggregates of α Synuclein (aSyn), an intrinsically disordered, single domain protein. Its gain of toxic function has been largely linked to PD development and progress. However, the identity of aSyn toxic species remains elusive. Several genetic alterations in its coding gene, SNCA, have been reported in familiar dominant forms of PD. However, their penetrance is very minor among patients, while oxidative stress remains as a general risk factor within all neurodegenerative diseases. In this context, several oxidative stress related post-translational modifications (PTMs) could act as possible modulators of the aSyn´s structural features and its physiopathology, and, therefore, may be responsible of triggering aSyn´s pathological role towards neurons and/or glial cells.We explored a series of oxidative modifications on recombinant aSyn induced by a photo-tunable method based on Ru complex 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 aSyn. We isolated and characterized these proteins variants by mass spectrometry to quantitate the degree of modification, the PTMs positions and exposure of Tyr residues under different conformational states, highlighting its impact on aSyn´s susceptibility. Initial biochemical and cytotoxicity characterization of modified species, as well as their effect on amyloid aggregation and membrane binding of aSyn will be presented.

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