The Prion Protein Regulates Synaptic Transmission by Controlling the Expression of Proteins Key to Synaptic Vesicle Recycling and Exocytosis

The cellular prion protein (PrPC), whose misfolded conformers are implicated in prion diseases, localizes to both the presynaptic membrane and postsynaptic density. To explore possible molecular contributions of PrPC to synaptic transmission, we utilized a mass spectrometry approach to quantify the release of glutamate from primary cerebellar granule neurons (CGN) expressing, or deprived of (PrP-KO), PrPC, following a depolarizing stimulus. Under the same conditions, we also tracked recycling of synaptic vesicles (SVs) in the two neuronal populations. We found that in PrP-KO CGN these processes decreased by 40 and 60%, respectively, compared to PrPC-expressing neurons. Unbiased quantitative mass spectrometry was then employed to compare the whole proteome of CGN with the two PrP genotypes. This approach allowed us to assess that, relative to the PrPC-expressing counterpart, the absence of PrPC modified the protein expression profile, including diminution of some components of SV recycling and fusion machinery. Subsequent quantitative RT-PCR closely reproduced proteomic data, indicating that PrPC is committed to ensuring optimal synaptic transmission by regulating genes involved in SV dynamics and neurotransmitter release. These novel molecular and cellular aspects of PrPC add insight into the underlying mechanisms for synaptic dysfunctions occurring in neurodegenerative disorders in which a compromised PrPC is likely to intervene.