INVESTIGADORES
SOCIAS Sergio Benjamin
congresos y reuniones científicas
Título:
Glycosaminoglicans may link tau amyloid aggregation and abnormal phosphorylation
Autor/es:
MEDINA L.; VERA C.; GONZALES LIZARRAGA, MF; SEQUEIRA S.; BARBOSA L.; SOCIAS, S.B.; ITRI R.; RAISMAN VOZARI R.; PAPY GARCÍA D.; CHANTEPIE S.; CHEHÍN R.
Lugar:
San Miguel de Tucumán
Reunión:
Congreso; III Latin American Federation of Biophysical Societies (LAFeBS); 2016
Institución organizadora:
Sociedad Argentina de Biofísica
Resumen:
Tau is a microtubule-associated protein that plays a crucial role in regulating microtubule dynamics, axonal transport and neurite outgrowth. In physiological conditions, these functions are regulated by site-specific phosphorylation. In pathological conditions, abnormal phosphorylation and amyloid aggregation lead to the formation of neurofibrillary tangles (NFT), a neuropathological hallmark in Alzheimer´s disease brain. The relationship between phosphorylation and aggregation is not well understood and could be essential to understand the toxic transition of Tau. In this work we study extracellular glycosaminoglicans as the link between phosphorylation and amyloid aggregation. In Alzheimer´s disease, heparan sulphate (HS) accumulates at the intracellular level in neurons co-localizing with NFT, while they persist at the neuronal cell membrane in normal brain. It is described that the presence of glycosaminoglycans is needed to achieve the pathological phosphorylation profile. Using fluorescence and SAXS spectroscopy we analyzed tau conformational changes alone and in the presence of these sugars in order to understand the molecular events leading to aggregation. The protein alone Is not prompt to aggregate, remaining stable over the time. In the presence of heparin, aggregation as monitored by ThT follows a sigmoidal kinetics. However, this behavior is not seen with HS. Surprisingly, SAXS data showed difference between heparin and HS prefibrillar aggregates. In vitro phosphorylation assays were performed using GSK3-β in presence of heparin and HS. Significant differences between both glycosaminoglycans were observed in the abnormal phosphorilation profile. These results strongly suggest that specific glycosaminoglycans are able to induce conformational changes in Tau leading to abnormal phosphorylation and generation of novel toxic oligomeric species