CONICET | Buscador de Institutos y Recursos Humanos

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme that has been associated to neurodegenerative diseases since it colocalizes with alpha synuclein in amyloid aggregates in post-mortem tissue of patients with sporadic Parkinson disease. In a previous work, we showed that glycosaminoglycans-induced GAPDH prefibrillar specie accelerate the conversion of alpha synuclein to fibrils. However, it remained to be determined whether the interplay between glycosaminoglycans, GAPDH and alpha synuclein has a role in pathological states. Here we demonstrate that the toxic effect exerted by alpha synuclein oligomers in dopaminergic cell culture was abolished in the presence of GAPDH prefibrillar species. We have performed a structural characterization of the protective species by using a combination of experimental and theoretical techniques obtaining the first allatom model of a GAPDH protofibril. According to our results, the protofibril is cylinder-shaped where the GAPDH subunits are arranged into layers of hexamers stacked along the cylinder long axis with an helical twist that gives rise to a repeating structure every twelve layers. This model was validated by crosslinking coupled to mass spectrometry experiments. Considering that GAPDH could also be secreted outside the cell where glycosaminoglycans are present, it seems plausible that GAPDH protofibrils could be assembled in the extracellular space kidnapping the alpha synuclein toxic oligomers. Thus, the role of this novel specie in the neuronal proteostasis must be studied. The data reported herein could open alternative ways in development of therapeutic strategies against synucleinopathies like Parkinson disease

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