Evidence of presynaptic location and function of the prion protein

The prion protein (PrPC) is a copper-binding protein of unknown function th at plays an important role in the etiology of transmissible spongiform ence phalopathies. Using morphological techniques and synaptosomal fractionation methods, we show that PrPC is predominantly localized to synaptic membrane s. Atomic absorption spectroscopy was used to identify PrPC-related changes in the synaptosomal copper concentration in transgenic mouse lines. The sy naptic transmission in the presence of H2O2, which is known to be decompose d to highly reactive hydroxyl radicals in the presence of iron or copper an d to alter synaptic activity, was studied in these animals. The response of synaptic activity to H2O2 was found to correlate with the amount of PrPC e xpression in the presynaptic neuron in cerebellar slice preparations from w ild-type, Prnp(0/0), and PrP gene-reconstituted transgenic mice. Thus, our data gives strong evidence for the predominantly synaptic location of PrPC, its involvement in the regulation of the presynaptic copper concentration, and synaptic activity in defined conditions.