The GM1 ganglioside induces toxic prefibrillar α-synuclein amyloid oligomers.

C. VASTI; RODRIGUEZ P; FIDELIO G

Congreso; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; 2021

Sociedad Argentina de Biofísica

Parkinson?s disease (PD) is an age-related disorder characterized by the presence of amyloid deposits of the 140-amino-acid protein AS (α-synuclein). AS fibrillation, the process of native soluble proteins misfolding into insoluble fibrils comprising cross-β-sheets, involving transient prefibrillar species with different biophysical features. In vitro evidence suggests that pre-fibrillar species (oligomeric intermediates), rather than mature amyloid fibrils, are likely to be the primary pathogenic agents in neurodegenerative diseases.We previously demonstrated that oligoGM1 (the oligosaccharide soluble portion of GM1 ganglioside) stimulated the formation of amyloid fibrils as compared to GM1 ganglioside which reduces AS aggregation. The morphological analysis showed that AS fibrils are lower in height in the presence of oligoGM1 compared to AS fibrils and we visualized structures compatible with AS oligomers in the presence of GM1.In this report, by using dot blot and atomic force microscopy (AFM), we demonstrated that GM1 stimulates the formation of oligomeric structures of AS in vitro.Furthermore, we verified that, in the presence of GM1, aggregation kinetics (followed by Thio T fluorescence) is lower respect to oligoGM1. Through this analysis, we confirmed that oligoGM1 accelerates the fibrillation of AS.Finally, cytotoxicity assay with cell culture of human SH-SY5Y neuroblastoma cells, demonstrated that oligomers obtained in the presence of GM1 have a higher cytotoxicity than AS fibers formed both in the absence or presence of oligoGM1.The results obtained contribute to the hypothesis recently emerged that demonstrate that the extent of fibrillary amyloid plaque deposition not correlate with neurodegenerative disease pathogenesis.