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

AVILA C.; TORRES-BUGEAU C.; BARBOSA L.; MORANDÉ SALES E.; OUIDJA O.; SOCIAS B.; RAISMAN VOZARI R.; PAPY GARCÍA; ITRI R.; CHEHÍN R.

Congreso; Reunión Anual de la Sociedad Argentina de Biofísica; 2013

SAB

Oligomeric arrangement of -synuclein has been associated to neuronal cell loss in neurological diseases. Although -SNis mainly found in the cytosol, the presence of misfolded or aggregated - SNoutside 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 - SN amyloid aggregates in PD. However, it remained to be determined whether the interplay between GAGs, GAPDH and -SN may exert a protective or a deleterious role on the development or evolution of PD. We demonstrate that -synuclein 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 s pectrometry. 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 -SN displaying an important role in cellular proteostasis.