Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing alpha-synuclein Oligomeric Species Toxicity

ÁVILA CL; TORRES-BUGEAU CM; BARBOSA LRS; MORANDÉ SALES E; OUIDJA MO; SOCÍAS SB; CELEJ MS; RAISMAN-VOZARI R; PAPY-GARCIA D; ITRI R; CHEHIN RN

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: Bethesda, Maryland; Año: 2014 vol. 289 p. 13838 - 13838

lyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme that has been associated to neurodegenerative diseases. GAPDH colocalizes with α-synuclein 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 glycosaminoglycans-induced GAPDH prefibrilar species accelerates the conversion of α-synuclein to fibrils. However, it remained to be determined whether the interplay among glycosaminoglycans, GAPDH and α-synuclein has a role in pathological states. Here we demonstrate that the toxic effect exerted by α-synuclein oligomers in dopaminergic cell culture is abolished in the presence of GAPDH prefibrilar species.Structural analysis of prefibrilar GAPDH performed by Small angle  X-ray scattering, showed a particle compatible with a protofibril. This protofibril is shaped as a cylinder 22 nmlong and cross-sect