Thank You Spain..... Dysfunction of the PI3K-Akt-GSK-3 pathway is a common feature in cell culture and in vivo models of prion disease. ncbi.nlm.nih.gov/pubmed/23741998 Neuropathol Appl Neurobiol. 2013 Jun 6. doi: 10.1111/nan.12066. [Epub ahead of print] Simon D, Herva ME, Benitez MJ, Garrido JJ, Rojo AI, Cuadrado A, Torres JM, Wandosell F. Source Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Unv. Autónoma de Madrid, 28049 Madrid, Spain. Abstract AIMS: Transmissible spongiform encephalopathies, also called prion diseases, are characterized by the cerebral accumulation of misfolded prion protein (PrPSC ) and subsequent neurodegeneration. However, despite considerable research effort, the molecular mechanisms underlying prion-induced neurodegeneration are poorly understood. Here, we explore the hypothesis that prions induce dysfunction of the PI3K/Akt/GSK-3 signalling pathway. METHODS: We employed two parallel approaches. Using cell cultures derived from mouse primary neurons and from a human neuronal cell line, we identified common elements that were modified by the neurotoxic fragment of PrP106-126 . These studies were then complemented by comparative analyses in a mouse model of prion infection. RESULTS: The presence of a polymerized fragment of the prion protein (PrP106-126 ) or of a prion strain altered PI3K-mediated signalling, as evidenced by Akt inhibition and GSK-3 activation. PI3K activation by the addition of insulin or the expression of a constitutively-active Akt mutant restored normal levels of Akt and GSK-3 activity. These changes were correlated with a reduction in caspase activity and an increase in neuronal survival. Moreover, we found that activation of caspase 3, Erk and GSK-3 are common features of PrP106-126 -mediated neurotoxicity in cellular systems and prion infection in the mouse cerebellum, while activation of caspase 12 and JNK was observed in cellular models. CONCLUSIONS: Our findings in cell culture and in vivo models of prion disease demonstrate marked alterations to the PI3K/Akt/GSK-3 pathway and suggest that two additional pathways contribute to PrP-induced neurotoxicity as responsible of JNK and Caspase 12 activation..
Posted on: Sun, 09 Jun 2013 18:39:46 +0000
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