INVESTIGADORES
CHEHIN Rosana Nieves
artículos
Título:
Characterization of heparin-induced glyceraldehyde-3-phosphate dehydrogenase early amyloid-like oligomers and their implication on α-synuclein aggregation.
Autor/es:
TORRES-BUGEAU CM; AVILA CL,; RAISMAN-VOZARI R, ; PAPY-GARCIA D, ; ITRI R, ; BARBOSA LR,; CORTEZ LM,; SIM VL, ; CHEHÍN, R
Revista:
JOURNAL OF BIOLOGICAL CHEMISTRY
Editorial:
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Referencias:
Año: 2012 vol. 20 p. 2398 - 23409
ISSN:
0021-9258
Resumen:
Lewy bodies and Lewy neurites, the neuropathological hallmarks of several neurological diseases, are mainly made of filamentous assemblies of α-synuclein. However, other macromolecules including tau, ubiquitin, glyceraldehyde-3-phosphate dehydrogenase and glycosaminoglycans are routinely found associated with these amyloid deposits. Glyceraldehyde-3-phosphate dehydrogenase is a glycolytic enzyme that can form fibrillar aggregates in the presence of acidic membranes but its role in Parkinson´s disease is still unknown. In this work, the ability of heparin to trigger the amyloid aggregation of this protein at physiological conditions of pH and temperature is demonstrated by infrared and fluorescence spectroscopy, dynamic light scattering, small angle X-Ray scattering, circular dichroism and fluorescence microscopy. Aggregation proceeds through the formation of short rod-like oligomers, which elongates in one-dimension. Heparan sulphate was also capable of inducing glyceraldehyde-3-phosphate dehydrogenase aggregation, but chondroitin sulphates A, B and C together with dextran sulphate had negligible effect. Aided with molecular docking simulations a putative binding site on the protein is proposed providing a rational explanation for the structural specificity of heparin and heparan sulphate. Finally, it is demonstrated that in vitro the early oligomers present in the glyceraldehyde-3-phosphate dehydrogenase fibrillation pathway promote α-synuclein aggregation. Taking into account the toxicity of α-synuclein prefibrillar species, the heparin-induced glyceraldehyde-3-phosphate dehydrogenase early oligomers might come in useful as a novel therapeutic strategy in Parkinson´s disease and other synucleinophaties