| dc.description.abstract | Neuronal cell death is the main event of neurodegenerative diseases, so to find out the molecular
mechanisms by which the death is being executed, would be very important to develop therapies against
these disorders.
A kinase which has been involved in neuronal death by apoptosis generation is Glycogen synthase kinase
3, although the mechanisms induced by this protein to facilitate apoptosis remain still unknown. The
present study has addressed this question by analysing the GSK3 contribution to apoptosis in two models
of neuronal death, one induced by inhibition of PI3K (LY294002 treatment) and the other generated by
exposing to prion. In the last one, as the same as LY294002-treated cells, we found that inhibition of Akt,
which led to activation of GSK3, took place during prion-induced neuronal death. In this regard, we
showed that overexpression of an active version of Akt avoided the death induced by PrP106-126,
pointing out that Akt dysfunction could be the first cause for prion-induced death. We suggested that the
peptide PrP106-126 interferes with insulin/IGF-1 receptor, inducing the PI3K/Akt pathway dysfunction.
In both models, the involvement of other pathways than PI3K/Akt/GSK3 has been evaluated. Thereby,
we also observed that activation of JNK was a common event in the two systems of neuronal death.
However, JNK did not significantly contribute to death in the LY294002-treated neuronal cells in contrast
to prion- treated cells.
Previously, we examined some features of the GSK3 regulation, particularly the activity modulation by
phosphorylation. Phosphorylation in Serine 21/9 leads to inactivation of the kinase, however
phosphorylation in Tyrosine 279/216 implies its activation. The mechanism by which Serine 21/9 is
phosphorylated are well known, nevertheless how Tyrosine 279/216 is phosphorylated is not yet fully
understood. Recently, auto-phosphorylation has been proposed to be the procedure for phosphorylating
Tyrosine 279/216. In this study, we have demonstrated that auto-catalysis is not the only way to
phosphorylate Tyrosine 279/216. Thus, we have verified the implication of phosphatases and kinases in
the regulation of phosphorylation of Tyrosine 279/216.
This and other studies corroborate the role of GSK3 in apoptotic neuronal death, therefore another aim of
this essay is to search GSK3 inhibitors with a potential therapeutical use for neurodegenerative disorders.
Thus, the development of an in vitro system of screening among a set of compounds allowed us to choose
the best candidates for inhibiting GSK3 in a cellular model. So, it seems highly likely that these selected
compounds will be the finest inhibitors for being used in vivo. | en |
