Functional role of cellular prion protein in regulating cell adhesion molecule associated transport systems under physiological and pathophysiological conditions

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The pathogenic form of prion protein (PrPsc) plays a crucial role in the development of spongiform encephalopathies, while the cellular form of PrP (PrPc) has protective functions against oxidative stress, hypoxia, ischemia, excitotoxicity or hypoglycemia. PrPc beneficially sustains neurotransmitter systems, in particular the serotonergic and dopaminergic systems, which are negatively affected by PrPsc. Hence, we will study whether PrPc regulates the uptake of tryptophan and tyrosine which are the precursor for serotonin and dopamine synthesis being important neurotransmitters in emotional homeostasis. Since we showed that PrPc regulates uptake of glutamate and cysteine into astrocytes and since both are required for synthesis of antioxidant glutathione, we also want to analyze whether PrPc regulates glutathione synthesis being essential for the defense of neurons against oxidative stress, including the vulnerable dopaminergic neurons, the abolition of which lead to Parkinson’s disease with its emotional disturbances. Since our results also indicated that PrPc regulates the release of lactate from astrocytes - a mechanism that comes into play under stress conditions - we want to further analyze the role of PrPc in regulating lactate transport from astrocytes to neurons under oxidative stress, with the question whether neuroprotective molecules may be conveyed from astrocytes to neurons via exosomes that have previously been shown to shuttle PrPsc between neural cells. We now propose to investigate whether exosomes PrPc-carrying convey beneficial molecules to prevent neuronal cell death.