INVESTIGADORES
BOLLO Mariana Ines
congresos y reuniones científicas
Título:
PERK signalling activated by GM2 accumulation
Autor/es:
VIRGOLINI, M.J. AND BOLLO M
Reunión:
Congreso; Reunión Annual XLVIII de la Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular (SAIB); 2012
Resumen:
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The accumulation of misfolded proteins into the Endoplasmic
Reticulum (ER) activates a signal transduction cascade called Unfolding Protein
Response (UPR), which attempts to restore homeostasis in the organelle. (PKR)-like-ER kinase (PERK) is an early
stress response element that attenuates protein synthesis. We demonstrated that Calcineurin (CN) associates
with PERK, enhancing inhibition of protein translation and cell viability (Plos
One 5:8e11925).
But
deregulation of UPR or prolonged ER stress promotes apoptotic cell death. PERK
signalling, including proapoptotic transcription regulator Chop induction,
persists under prolonged ER 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. We hypothesized that PERK activation
participates in the pathogenesis of GM2-gangliosidosis. Here, we show a
significant uptake of GM2 in N2A neurons loaded with exogenous ganglioside. In
addition, thin
layer chromatography and immunocytochemistry approaches
revealed a pool of intracellular GM2 localized in the ER. Moreover, the
abnormal ganglioside accumulation induces PERK activation, and provokes up-regulation
of either CN or CHOP, at different time points.
