The research activity of our group aims to define the neurodevelopmental functions of the PDK1 signaling network and itsconsequences to neurodegenerative and mental disease.
For that, we aim to:
- Investigate whether the PDK1 K465E mice is protectedfrom Alzheimer Disease. In the PDK1 K465E knock-in mice, reduced activation of Akt caused subtle morphogeneticdefects that did not lead however to adverse behavioral outputs. We learned that the hypomorphic reduction of the Akt axis protected these mice from a number of insults disrupting homeostasis, which might singularly be also protected from neurodegeneration.
- Define the contribution of the PDK1 substrates different from Akt to mental disease. In the PDK1 L155E mice, disruption of PDK1 signaling with otherwise intact Akt activity caused profound defects in the patterning of the central nervous system, leading to severe mental disorders reminiscent of human schizophrenia.
To understand the importance that the dysfunction of the mechanisms of signal transduction might play in brain pathology. We focussed on the PI 3-kinase/Akt signaling pathway, which controls essential roles during neuronal development and is deregulated in different mental disorders. We generated brain-specific conditional knock-in mice expressing two distinct rationally designed, crystal structurebased, point mutant forms of the PDK1 kinase, a master hub on this signaling pathway. In the PDK1 K465E mice, activation of Akt is selectively impaired, whereas in the PDK1 L155E mice, activation of most of the effectors of this signaling axis including S6K, RSK, SGK, and PKC, but not Akt, is abolished.
