Cellular and Molecular Neurobiology
Author: William Queiroz Felippe | Email: william.queiroz@unr.edu.ar
William Queiroz Felippe1°, Phelippe Do Carmo Gonçalves1°,Christian Griesinger2°, Claudio Oscar Fernandez1°
1° Max Planck Laboratory for Structural Biology, Chemistry, and Molecular Biophysics of Rosario (MPLbioR, UNR-MPINAT))
2° Max Planck Institute for Multidisciplinary Sciences, Department of NMR-based Structural Biology, Am Fassberg 11, 37077 Göttingen, Germany
Neurodegeneration in Parkinson´s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra and by the presence of amyloid fibrillar cytoplasmic aggregates, known as Lewy bodies, in multiple brain regions, containing the protein alpha-synuclein (aS). Growing evidence supports a link between brain copper homeostasis, the formation of aS-copper complexes and the development of PD. Protein-metal interactions play an important role in aS aggregation and might represent a link between the pathological processes of protein aggregation, oxidative damage in the brain and neuronal cell loss. Indeed, the role of copper ions in aS amyloid assembly and neurodegeneration became a central question in the pathophysiology of PD. The identity of the Cu(I) binding ligands at Met-X3-Met site of aS and its role into the affinity and structural properties of the interaction were elucidated by our group using NMR spectroscopy. We found that the formation of aS-Cu(I) complex at the N-terminal region stabilizes local conformations with α-helical secondary structure and restricted motility. In this work we have extended our research towards the metallobiology of PD, analysing the impact of aS-Cu(I) complexation and its structural consequences on aS membrane binding and aggregation. Overall, our findings open new avenues of investigations into the metallobiology of PD, reshaping the consideration of copper mediated pathology in vivo.