Premium
Dysfunction of the PI 3 K – Akt – GSK ‐3 pathway is a common feature in cell culture and in vivo models of prion disease
Author(s) -
Simon D.,
Herva M. E.,
Benitez M. J.,
Garrido J. J.,
Rojo A. I.,
Cuadrado A.,
Torres J. M.,
Wandosell F.
Publication year - 2014
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12066
Subject(s) - protein kinase b , neurodegeneration , neurotoxicity , microbiology and biotechnology , biology , pi3k/akt/mtor pathway , cell culture , mapk/erk pathway , signal transduction , chemistry , genetics , medicine , disease , organic chemistry , pathology , toxicity
Aims Transmissible spongiform encephalopathies, also called prion diseases, are characterized by the cerebral accumulation of misfolded prion protein ( PrP SC ) 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 PI 3 K / Akt / GSK ‐3 signalling pathway. Methods 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 106–126 . 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 ( PrP 106–126 ) or of a prion strain altered PI 3 K ‐mediated signalling, as evidenced by Akt inhibition and GSK ‐3 activation. PI 3 K 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 106–126 ‐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 PI 3 K / Akt / GSK ‐3 pathway and suggest that two additional pathways contribute to PrP ‐induced neurotoxicity as responsible of JNK and caspase 12 activation.