007 | Variant Y39E of alpha-synuclein: Structural insights and aggregation properties

Cellular and Molecular Neurobiology

Author: Nicola Martina Böffinger | Email: nboeffinger@cei-mplbior.unr.edu.ar

Nicola Böffinger , Stefan Eimer , Claudio O. Fernández , Christian Griesinger

1° Max Planck Laboratory for Structural Biology, Chemistry, and Molecular Biophysics of Rosario (MPLbioR, UNR-MPINAT), Partner Laboratory of the Max Planck Institute for Multidisciplinary Sciences (MPINAT, MPG). Centro de Estudios Interdisciplinarios, Universidad Nacional de Rosario, Rosario, Argentina.
2° Max Planck Institute for Multidisciplinary Sciences, Department of NMR-based Structural Biology, Am Fassberg 11, 37077 Göttingen, Germany.
3° Goethe University, Frankfurt, Germany

Altered protein aggregation and accumulation is associated with different neurodegenerative diseases such as Creutzfeldt-Jakob’s, Alzheimer or Parkinson disease (PD). The latter is classified as synucleinopathy, which is characterized by the abnormal aggregation and accumulation of α-synuclein (αSyn), forming oligomers and fibrils. Less is known about the toxic species of αSyn aggregates. However, with regards to its aggregation it has been discovered that next to the central non-amyloid β-component region (NAC) of αSyn further N-terminal regions are crucial. One of these regions expands over residues 36-42, whose elimination prevents protein aggregation. Y39 is located within this region and was found to be phosphorylated in advanced stages of PD. The mutation Y39E imitates this phosphorylation and allows to study its impact on protein aggregation and toxicity. Using biophysical methods such as NMR and circular dichroism amongst others we found that the Y39E αSyn variant has a different aggregation profile compared to the wild-type species. NMR studies revealed that that the structural features of Y39E αSyn, at a monomeric level, does not differ significantly from WT αSyn, thus changes in aggregation from the transition of monomers into oligomers and/or fibrils are likely due the loss of function of Tyr at position 39 of the protein. Results focused on membrane binding and toxicity in cell and animal models for αSyn aggregation validate the measurements performed in vitro.