Chemical chaperone reduces Endoplasmic Reticulum Stress in a GM2-gangliosidosis cell model

FERNÁNDEZ M; VIRGOLINI M.J.; BOLLO M

Congreso; XXXIII Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; 2018

Sociedad Argentina de Neurociencias (SAN)

Chemical chaperone reduces Endoplasmic Reticulum Stress in a GM2-gangliosidosis cell modelThe 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. PERK is an early ER stress sensor that attenuates protein synthesis. We demonstrated 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 due to deficiency in β-hexosaminidase activity. However, the mechanisms that determine how GM2 accumulation triggers neuronal cell death remain unknown. Recently, we demonstrated in primary cultured neurons, that GM2 accumulation induces ER Ca2+ depletion and, in turn activates PERK signaling, Here, we show that the selective PERK inhibitor GSK2606414 as well as CN and CHOP knockdown, effectively modulate neurite atrophy and apoptosis induced by GM2 accumulation. Moreover, we determinate that, the chemical chaperone UDCA (acid ursodesoxicolic) protects neuroblastoma cells Neuro 2a (N2a) againts ER stress, decreasing CHOP expression as well as the susceptibility of neurons to undergo apoptosis.