INSIBIO   05451
INSTITUTO SUPERIOR DE INVESTIGACIONES BIOLOGICAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Glyceraldehyde-3-phosphate deshydrogenase early oligomers can alter the alpha-synuclein aggregation kinetics: role of Glycosaminoglycans .
Autor/es:
ROSANA CHEHÍN
Lugar:
Yerba Buena
Reunión:
Workshop; Workshop on Potein Dynamics and Reactivity.; 2011
Institución organizadora:
CEBANOA/DAAD
Resumen:
Lewy bodies and Lewy neurites, neuropathological hallmarks
of several neurological diseases, are mainly made of filamentous
assemblies of -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 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 sulfate was also capable of inducing
glyceraldehyde-3-phosphate dehydrogenase aggregation, but
chondroitin sulfates A, B, and C together with dextran sulfate
had a 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 sulfate. Finally, it is demonstrated that
in vitro the early oligomers present in the glyceraldehyde-3-
phosphate dehydrogenase fibrillation pathway promote
-synuclein aggregation. Taking into account the toxicity of
-synuclein prefibrillar species, the heparin-induced glyceraldehyde-
3-phosphate dehydrogenase early oligomers might
come in useful as a novel therapeutic strategy in Parkinson
disease and other synucleinopathies