Structural characterization of GAPDH protofibrils formed in the presence of acidic membranes

AVILA, CL; TORRES-BUGEAU, CM; VERA, C; GONZALEZ-LIZARRAGA, MF; BARBOSA, LRS; RAISMAN-VOZARI R; PAPY-GARCIA, D; ITRI, R; CHEHIN, RN

Sierra de la Ventana

Congreso; XLIII Reunion Anual de la Sociedad Argentina de Biofisica; 2014

Sociedad Argentina de Biofisica

Parkinson disease is characterized by the loss of dopaminergic neurons. Cell death has been attributed to certain oligomeric intermediates formed during the aggregation pathway of alfa-synuclein (AS), which can alter membrane permeability and promote mitochondrial, proteasomal and membrane trafficking dysfunction. Experiments on SH-SY5Y cells showed that the toxicity exerted by AS could be abolished by protofibrilar species of Glyceraldehide-3-phosphate dehydrogenase (GAPDH) formed in the presence of glycosamineglycanes. This mechanism for the mitigation of AS toxicity might be relevant at the extracellular space, where both GAPDH and glycosamineglycanes are present, inhibiting the spreading of the disease. During aging, certain changes could affect the normal functioning of this protective pathway, facilitating the onset of Parkinson disease. We described how GAPDH aggregation can also be triggered by the presence of negatively charged lipidic membranes. This data acquires relevance in the light of recent reports associating the overexpression of phospholipase D to neurodegenerative disease during aging. In this workwe show that the increase of phosphatidic acid in the lipid membrane could drive the aggregation of GAPDH through a different pathway. We show that the protofibrils formed in this pathway are structurally different from the protective pathway and incapable of binding AS. In this way, we propose that an increase in phospholipase D levels would result in a depletion of the extracellular GAPDH available to form neuroprotective species contributing to the onset of the Parkinson disease during aging.