A cell-based model for αS aggregation in Parkinson disease: Testing the correlation between structural and cellular biology

BURATTI, FIAMMA A.; GENTILE, IÑAKI; GARRO, HUGO A.; RAMUNNO, CARLA F.; GONZALEZ, NAZARENO; NIGENDA EZEQUIEL; FERNÁNDEZ, CLAUDIO O.

Congreso; Reunión Científica Anual de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2019

The discovery of aggregation inhibitors and the mechanism elucidation are key in the quest to mitigate the toxic consequences of amyloid formation. Previous studies of the antiamyloidogenic mechanism of action of sodium phtalocyanine tetrasulfonate (PcTS) on α-Synuclein (αS), demonstrated that specific aromatic interactions are fundamental for the inhibition of amyloid assembly. Here we studied the influence of structural modifications on the activity of tetrapyrrolic compounds on αS aggregation. For the first time, our laboratory has extended the studies in the field of the bioinorganic chemistry and biophysics to cellular biology using a well-established cell-based model to study αS aggregation. Binding modes of the tetrapyrrole ligands to αS are determined by the planarity and hydrophobicity of the aromatic ring system in the tetrapyrrolic molecule and/or the preferential affinity of the metal ion conjugated at the center of the macrocyclic ring. The different capability of these compounds to modulate αS aggregation in vitro was reproduced in cell-based models of αS aggregation, demonstrating unequivocally that the modulation exerted by these compounds on amyloid assembly is a direct consequence of their interaction with the target protein.