INVESTIGADORES
CHEHIN Rosana Nieves
congresos y reuniones científicas
Título:
Structural characterization of membrane-induced GAPDH prefibrillar species and its implications in Parkinson disease
Autor/es:
TORRES BUGEAU, CLARISA; AVILA CL,; GONZALEZ-LIZARRAGA, MF; VERA, C; BARBOSA LR,; ITRI R,; CHEHÍN RN
Lugar:
Catxambu
Reunión:
Congreso; XXIX Reunion Anual FESBE; 2014
Institución organizadora:
Federacion de Sociedades de Biologia Experimental
Resumen:
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme that has been associated to neurodegenerative diseases. GAPDH colocalizes with alfa-synuclein (AS) in amyloid aggregates in post-mortem tissue of patients with sporadic Parkinson disease and promotes the formation of Lewy body-like inclusions in cell culture. In a previous work, we showed that in vitro heparin can trigger GAPDH amyloid aggregation and that prefibrillar species present during the aggregation process can modify the AS aggregation kinetic. The heparin-induced GAPDH prefibrillar species are capable to abolish the toxicity of AS species in cell cultures. The GAPDH prefibrillar species responsible for this activity were structurally characterized as protofibrils. We have also demonstrated that acidic membranes can trigger the GAPDH amyloid aggregation. However, structural and functional features of membrane-induced GAPDH prefibrillar species were not studied, and thus, its effectiveness on AS aggregation kinetic is unknown. Objectives: The aim of the present work is to perform a structural and functional characterization of membrane-induced GAPDH prefibrillar species, and to compare them to heparin-induced GAPDH prefibrillar species. Methods: The work does not involve animal or human experiments. Structural characterization of GAPDH prefibrillar species was performed using Fourier transform (FT-IR) together with Small Angle X-Ray Scattering (SAXS). Biocomputational techniques were used to obtain a model of GAPDH-membrane interaction. Results: In this work we demonstrated that membrane-induced and heparin-induced GAPDH prefibrillar species are structurally different. This suggest that aggregation evolves through different pathways. Aggregation was seen to be dependent on membrane composition, curvature and fluidity. Using biocomputational techniques we modeled GAPDH:membrane interaction. We observed that both hydrophobic and electrostatic forces drive the aggregation process induced by membranes . On the contrary, heparin induced aggregation was driven mainly by electrostatic forces. These differences arising during the first steps of aggregation, could explain the differences in the aggregation pathway. Conclusion: Since neuronal membrane composition changes during aging, studying the impact of these changes on protein aggregation becomes mandatory. The data reported herein sheds light into the impact of membrane composition and physical state on protein aggregation. It also helps understand some mechanisms involved in the first steps of this process. The model provided herein might prove useful in the development of therapeutic strategies against synucleinopathies like Parkinson´s disease.