INVESTIGADORES
CHEHIN Rosana Nieves
artículos
Título:
Structural Characterization of Heparin-induced GAPDH Protofibrils Preventing α-synuclein Oligomeric Species Toxicity
Autor/es:
AVILA CL, TORRES-BUGEAU CM, BARBOSA LR, MORANDÉ SALES E, OUIDJA MO, SOCÍAS SB, CELEJ MS, RAISMAN-VOZARI R, PAPY-GARCIA D, ITRI R, CHEHIN RN
Revista:
JOURNAL OF BIOLOGICAL CHEMISTRY
Editorial:
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Referencias:
Lugar: Bethesda, Maryland; Año: 2014
ISSN:
0021-9258
Resumen:
Glyceraldehyde-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 nm-long and cross-section diameter of 12 nm. Using biocomputational techniques we obtained the first all-atom model of the GAPDH protofibril, which was validated by cross-linking coupled to mass spectrometry experiments. Since GAPDH can be secreted outside the cell where glycosaminoglycans are present, it seems plausible that GAPDH protofibrils could be assembled in the extracellular space kidnapping α-synuclein toxic oligomers. Thus, the role of GAPDH protofibrils in neuronal proteostasis must be considered. The data reported herein could open alternative ways in development of therapeutic strategies against synucleinopathies like Parkinson's disease.