Design of a molecule capable of inducing the formation of neuroprotective protofibrils of GAPDH

BALEANI MÓNICA ANDREA; AVILA, CÉSAR LUIS; PAPY-GARCÍA DULCE; CHEHÍN, ROSANA NIEVES

Salto Grande

Congreso; Latin American Crosstalk in biophysics and phisiology; 2015

Seccional Biofísica- Sociedad Uruguaya de Biociencias y sociedad Argentina de biofísica

Parkinson disease (PD) is one of the most important neurodegenerative disorders with motor alterations resulting from the loss of dopaminergic neurons in the substantia nigra. The loss of neurons is caused by toxic oligomeric species of alfa-synuclein (AS). We demonstrated that AS oligomers can be recruited by protofibrillar species of Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) abolishing its toxic effect1. The formation of this neuroprotective GAPDH protofibril could be triggered in vitro by heparin. Since heparin has a strong anticoagulant activity, our goal is to find a compound capable of promoting GAPDH agregation without afecting the coagulation cascade. In this way using Thioflavin T assay we found several heparan-mimetics able to induce GAPDH aggregation. Using the liposomal leakage test we also evaluated the capability of GAPDH protofibril to prevent the disruption of reconstituted membrane by the AS oligomers. These results represent an important first step towards the development of neuroprotective compunds to be used in the treatment of PD.[1] Ávila CL, et al. J Biol Chem 289:13838-50, 2014.