Structural characterization of heparin-induced GAPDH protofibrils preventing alfa- synucleinoligomeric species toxicity

AVILA, CL; TORRES-BUGEAU, CM; BARBOSA, LRS; MORANDÉ SALES, E; OUIDJA, O; SOCÍAS, B; RAISMAN- VOZARI, R; PAPY-GARCIA, D; ITRI, R; CHEHÍN, R

Carlos Paz, Cordoba

Congreso; XLII Reunion Anual de la Sociedad Argentina de Biofisica; 2013

Sociedad Argentina de Biofisica

Oligomeric arrangement of alfa-synuclein (AS) has been associated to neuronal cell loss in neurological diseases. Although AS is mainly found in the cytosol, the presence of misfolded or aggregated AS outside the cell suggests that it might play a role also at the extracellular level. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glycosaminoglycans (GAGs) have been found associated to AS amyloid aggregates in PD. However, it remained to be determined whether the interplay between GAGs, GAPDH and AS may exert a protective or a deleterious role on the development or evolution of PD. We demonstrate that AS oligomers toxicity on cultured human dopaminergic neurons can be prevented by a newGAPDH specie formed in the presence of heparin. Structural characterization, performed by SAXS shows a cylinder-like specie with average size of 22 x 12 nmcompatible with a protofibril. Using computational modelling we obtained the first all-atom model of the GAPDH protofibril capable to satisfy all the experimental restrictions derived from SAXS and mass spectrometry. Moreover, we propose a pathway for GAPDH aggregation involving the loss of the tetrameric state of the enzyme with a concomitant appearance of native-like dimeric species, which quickly assemble to protofibrils. It seems plausible that heparansulphates from brain extracellular matrix can effectively interact with GAPDH and induce the formation of protofibrils able to scavenge AS displaying an important role in cellular proteostasis.