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Congreso; XXVIII Congreso Anual de Investigación Neurociencia y Reunión satélite/neurobiología del comportamiento: neuroetología y neurobiología de la memoria en el Conosur; 2013

Institución organizadora:

Sociedad Argentina de Neurociencia

Resumen:

The accumulation of misfolded proteins within the endoplasmic reticulum (ER) triggers a cellular process known as the Unfolded Protein Response (UPR), in which the cell attempts to restore ER homeostasis. If ER damage is persistent or excessive, an apoptotic response is initiated. It is well accepted that ER Ca2+ depletion induces ER stress. PERK is an early ER stress sensor that attenuates protein synthesis. We demonstrated in Xenopus oocytes that Calcineurin (CN) associates with PERK, enhancing inhibition of protein translation and cell viability. But, PERK signaling, including pro-apoptotic transcription factor CHOP, persists activated under prolonged stress. Chronic UPR is proposed to contribute to the pathology of many neurodegenerative diseases. GM2-gangliosidosis are characterized by a progressive neurodegeneration. However, the mechanisms that determine how GM2 accumulation triggers neuronal cell death remain unknown. Here, we report, by thin layer chromatography and immunocytochemistry approaches, that N2a neurons loaded with exogenous ganglioside, accumulates GM2 at ER membranes. The abnormal GM2 build-up induces PERK activation, and provokes up-regulation of either CN or CHOP, at different time points. This stress also decreases the ER calcium content in Fura2-loaded cells. Moreover, calcium depletion, as well as, Chop level increase, induced by GM2 accumulation, was enhanced by MBCD, a pharmacological agent that increase ganglioside delivery to the ER.