Cellular and Molecular Neurobiology

Author: Phelippe do Carmo Goncalves | Email: pgoncalves@cei-mplbior.unr.edu.ar

Phelippe do Carmo Gonçalves , Fiamma A. Buratti , Nicola Böffinger , Francisco Hita , Irina Fernández , Nicolás Esterlizzi , Federico Dhöle , Gisel Ayelen Lucia Kehoe , Guillermo Vaccaro , Stefan Eimer , Christian Griesinger , Claudio O. Fernandez

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.

Aberrant fibrillar aggregation of the protein α-synuclein (αS) is associated with Parkinson’s disease. Recently, studies have shown that molecular events related to the physiological and pathological roles of αS might be regulated by specific sequence motifs or even by a single residue. In this work, we have investigated structural details of the role of the Y39 residue in the context of aggregation and lipid binding properties by studying the wild-type protein (wt αS) and its site-directed mutants Y39F, Y39L, and Y39A. We found that the Y39F mutant exhibited a similar aggregation profile compared with wt αS, whereas the species containing the Y39L and Y39A mutations showed a significant decrease in the rate and amount of aggregated protein. H4 cellular model and animal model of C. elegans for αS aggregation validated the measurements performed in vitro. Furthermore, using NMR and circular dichroism, clear structural differences were observed between the vesicle-bound forms of the αS variants at the aggregation-prone hydrophobic domain (NAC). In light of our results, we conclude that the removal of aromatic residues at position 39 impairs the amyloid fibril formation of αS and the aromaticity at position 39 determines the membrane-bound conformation of αS by modulating lipid interactions involving the central hydrophobic NAC domain. Overall, our results shed light on the mechanistic basis behind aggregation, membrane damage, and cellular toxicity in amyloid diseases.