Dysfunction of the PI3K–Akt–GSK‐3 pathway is a common feature in cell culture and in vivo models of prion disease. Issue 3 (April 2014)

• Record Type: Journal Article
• Authors: Simon, D.; Herva, M. E.; Benitez, M. J.; Garrido, J. J.; Rojo, A. I.; Cuadrado, A.; Torres, J. M.; Wandosell, F.
• Is Part Of: Neuropathology & applied neurobiology. Volume 40:Issue 3(2014)
• Page Start: 311
• Page End: 326
• Publication Date: 2014-04
• Subjects: Nervous system -- Diseases -- Pathology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/nan.12066
• Languages: English
• ISSNs: 0305-1846

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="nan12066-sec-0001" sec-type="section"> <title>Aims</title> <p>Transmissible spongiform encephalopathies, also called prion diseases, are characterized by the cerebral accumulation of misfolded prion protein (PrP<sup>SC</sup>) 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.</p> </sec> <sec id="nan12066-sec-0002" sec-type="section"> <title>Methods</title> <p>We employed two parallel approaches. Using cell cultures derived from mouse primary neurones and from a human neuronal cell line, we identified common elements that were modified by the neurotoxic fragment of PrP<sup>106–126</sup>. These studies were then complemented by comparative analyses in a mouse model of prion infection.</p> </sec> <sec id="nan12066-sec-0003" sec-type="section"> <title>Results</title> <p>The presence of a polymerized fragment of the prion protein (PrP<sup>106–126</sup>) 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 PrP<sup>106–126</sup>‐mediated neurotoxicity in cellular systems and prion infection in the mouse cerebellum, while activation of caspase 12 and JNK was observed in cellular models.</p> </sec> <sec id="nan12066-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Our findings <italic>in cell culture</italic> and <italic>in vivo</italic> 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.</p> </sec> </abstract>