Cellular and Molecular Neurobiology
Author: Dayanne Martins da Silva | Email: dmartins@cei-mplbior.unr.edu.ar
Dayanne Martins 1°, Phelippe do Carmo Gonçalves 1°, Francisco Hita 1°, Daphne S. Cukierman 3°, Nicolás A. Rey 2°, Claudio O. Fernandez 1°, 1°, 1°, 1°, 1°
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° Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro, Brazil.
3° Department of General and Inorganic Chemistry, Institute of Chemistry, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
α-synuclein (αSyn) is an intrinsically disordered protein that can interact with physiological metal ions, a process which contributes to the pathological mechanism underlying Parkinson’s disease (PD). Exogenous metals have also been linked to PD through their action on protein aggregation and oxidative stress. Aluminum(III), in particular, constitutes a known neurotoxic agent. In addition to increase the production of reactive oxygen and nitrogen species, exposure to Al3+ also causes iron dyshomeostasis through amplified Fe3+/Fe2+ redox activity. In this context, the development of new drugs to preclude the accumulation of such metal ions is crucial to slowing down the progression of PD. In this work, we evaluated the interactions of αSyn and the ligand 2-hydroxy-3-methyl-benzaldehyde 3,4,5-trimethoxybenzoyl hydrazone (MTMP) with Al3+. Both binary and the ternary system were considered. The nature and affinity features of αSyn-metal complexation were described at a residue specific level of resolution, combined with studies focused on the metal sequestering potential of MTMP. Aggregation kinetics experiments correlated well with the αSyn-Al3+ interaction profile. Cell-based assays are currently underway to validate our findings in a cellular context and extend our studies to other experimental models of aluminum-related parkinsonism.