CONICET | Buscador de Institutos y Recursos Humanos

INVESTIGADORES

BOLLO Mariana Ines

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Título:

GM2-ganglioside accumulation mediates Endoplasmic Reticulum calcium depletion and PERK signaling activation

Autor/es:

VIRGOLINI MJ; VIRGOLINI, M.J. LOPEZ, PHH AND BOLLO M..; CAMBIASSO, MJ; BERBERIAN, P., BOLLO, M., ROBERTS G., DEGIORGIS, J., DIPOLO R. AND BEAUGE L.

Reunión:

Congreso; 51 Reunion Anual de la Sociedad Bioquimica y de Biologia Celular; 2015

Resumen:

The accumulation of misfolded proteins within theendoplasmic reticulum (ER) triggers a cellular process known as the UnfoldedProtein Response (UPR), in which the cell attempts to restore ER homeostasis. If ER damage is persistent or excessive, an apoptoticresponse is initiated. It is well accepted that ER calciumdepletion induces ER stress. PERK is anearly ER stress sensor that attenuates protein synthesis. We demonstrated that Calcineurin (CN)associates with PERK, enhancing inhibition of protein translation and cellviability. But PERK signaling, including pro-apoptotictranscription factor CHOP, persistsactivated under prolonged stress. Chronic UPR is proposed to contribute to the pathologyof many neurodegenerative diseases.GM2-gangliosidosis are characterized by a progressive neurodegeneration due todeficiency in b-hexosaminidase activity. However, the mechanisms that determine how GM2accumulation triggers neuronal cell death remain unknown.Material and Methods: N2Acells were either loaded with GM2 or treated with ShRNA specific for b-hexosaminidase. The GM2 accumulation in the ER was assessed by thinlayer chromatography and immunocytochemistry. Besides, we exanimated whetherUPR was activated using immunopresipitations, western-bloting and Ca2+measurements.Resultsand Discussion: We report that theGM2 accumulation in the ER induces PERK activation, and provokes up-regulationof either CN or CHOP, at different time points. This stress also decreases theER calcium content. Moreover, calcium depletion, as well as CHOP levelincrease, were enhanced by MBCD, a pharmacological agent that augmentganglioside delivery to the ER. This finding suggests that varied time courseof the individual PERK signaling elements influence the cell?s ultimate fate inresponse to abnormal GM2 accumulation.

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