S-007 | Modulation of early and late steps of αS aggregation and its impact on the morphological structural and toxic properties of amyloid fibrils

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

Phelippe do Carmo Gonçalves^1°, Irina Fernández^1°, William Queiroz Felippe^1°,  Juan Ignacio Torres^1°, Christian Griesinger^2°, Claudio O. Fernandez^1°2°

^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.

A plethora of evidences associates structural dysfunction of the protein alpha-synuclein (αS) and self-assembly into fibril species with the neuropathology of Parkinson’s disease (PD) and other synucleinopathies. Given the critical role played by αS amyloid assembly in PD, its aggregation pathway represents then an obvious target for therapeutic intervention. In that context, amyloid aggregation of αS was shown to be modulated by specific sequence motifs flanking the NAC region, where the pre-NAC segment 36GVLYVGS42 was shown to play a major role in driving αS aggregation into amyloid structures. Moreover, the sensitivity of the early stages of αS amyloid formation to specific sequences offers opportunities to control amyloid assembly. In this work, we have conducted experiments aimed to obtain high-resolution structural information of αS interactions on different steps of its aggregation landscape. Our strategy allowed us to investigate further how the early and late stages of αS aggregation modulate each other, offering an explanation of how the morphological and structural features of amyloid fibrils can be tuned by the binding of small molecules to specific sequences that modulate fibril formation, thereby rendering the resulting structures less-toxic. Overall, our work demonstrates that sequence-based binding of small molecules to monomeric αS could be executed into the design of therapeutic molecules for the treatment of PD.