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Characterization of Photo-induced Oxidative Modifications of α-Synuclein

Ezequiel Giménez

  • La Plata,
  • Argentina
  • Ezequiel Giménez ¹
  • , Gian Franco Cavazzutti ¹
  • , Andrés Martín Toscani ¹
  • , Thomas Jovin ²
  • , Henning Urlaub ³
  • , Lisandro Falomir Lockhart ¹
  • 1 Laboratorio de Neuroquímica y Biofísica de Enfermedades Neurodegenerativas, INIBIOLP-CONICET, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Argentina
  • 2 Laboratory of Cellular Dynamics, Max Planck Institute for Biophysical Chemistry. Göttingen, Germany.
  • 3 Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry. Göttingen, Germany.

A gain of toxic function of the protein α-Synuclein (aSyn) has been largely linked to the development and progress of Parkinson’s disease (PD) and related Synucleinopathies. However, the identity of aSyn toxic species remains elusive. In this way, post-translational modifications (PTMs) are a well-known source of variability of proteins ́ structure, function, and localization, and are therefore possible modulators of the physiopathology of aSyn in neurons. Our project aims for a better understanding of the initial molecular events leading to PD and the development of innovative tools for the early diagnosis of Synucleinopathies. For this purpose, we have optimized protocols to modify aSyn employing a photochemical method that uses Rutheniun (II) Tris(bipyridine) as photosensitizer. Particularly, we have generated, characterized, and quantified covalent cross-linked oligomers and nitrated species via fluorescence spectroscopy, and mass spectrometry. Since aSyn is an intrinsically disordered protein, it can adopt multiple conformations, depending on the environment and interacting partners. Therefore, we also applied photo-oxidation protocols to compare the susceptibility of aSyn to be modified when adopting helix-rich or cross β-sheets (fibrillar) structures. This is a first step towards the development of new strategies that could recognize and quantitate specific aSyn PTMs as early potential biomarkers of Synucleinopathies in complex biological samples.