GAPDH: unveiling the seeds of the disease

TORRES-BUGEAU, CLARISA M; AVILA CL; CORTEZ, LEONARDO; RAISMAN-VOZARI, RITA; PAPY-GARCIA, DULCE; CHEHIN, RN

Salta

Congreso; XXXIX Annual Meeting of the Argentinean Biophysical Society and 3rd Latin American Protein Society Meeting; 2010

Sociedad Argentina de Biofisica

Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) have common cellular and molecular mechanisms including protein aggregation. The aggregates usually consist of fibers containing misfolded proteins termed amyloid. These aggregates are composed mainly by Abeta peptide and alpha-synuclein in AD and PD respectively. However the presence of others proteins was also described. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a well-studied protein as a glycolytic enzyme. Nevertheless, current evidence reveals that this protein can form fibrillar aggregates which were found in the post mortem brains of patients with PD and AD. However, GAPDH is unable to form fibrillar aggregates at physiological pH and temperature conditions. Glycosaminoglycans (GAGs) are routinely found associated with amyloid deposits and the role of GAGs in amyloid fibril formation were reported. To determine whether the presence of GAGs can induce the GAPDH fibrillation, formation of fibrils were investigated in the presence of different GAGs and other polysaccharides. Differential aggregation kinetics of GAPDH in the presence of Heparin, Chondroitin sulfate, Dextran, and an oligomeric heparan sulfate mimetic named F6 were found. Heparin and F6 increase dramatically the aggregation rate as well as the yield of GAPDH amyloid fibril formation while Dextran and Chondroitin sulfate did not show any effect. Our results indicate that an imbalance in the GAG could trigger the process of GAPDH fibril formation resulting ultimately in an increased amount of Abeta peptide and alpha-synuclein aggregates. Previously reported changes in the GAG composition of aged brains could give relevance to these observations. In order to determine the implicance of GAPDH aggregation in PD and AD we studied the aggregation kinetics of Abeta peptide and alpha-synuclein in the presence of preformed GAPDH fibrils. Our results strongly suggest the ability of these fibrils to induce a seeding effect on both proteins. These results led to identify a GAPDH as a new hallmark protein in AD and PD disease. To confirm this hypothesis, small molecules with proven neurotrophic effects in dopaminergic neurons showed to act inhibiting the GAPDH aggregation exhibiting no effect on alpha-synuclein fibrillation.