The role of the prion protein in neurodegenerative disorders

The cellular prion protein (PrPC) is a cell surface glycoprotein mainly expressed in the central nervous system. A β sheet-reach conformer of PrPC generates the prion, the infectious particle causing prion diseases. The physiological role of PrPC remains enigmatic although it has been suggested that it could serve in cell survival, signal transduction, copper metabolism (Linden et al., 2008) and Ca2+ homeostasis (Lazzari et al., 2011). Recently it has been demonstrated that PrPC is a high-affinity receptor for amyloid-β (Aβ) fragments of the amyloid precursor protein implicated in Alzheimer’s disease (AD), and that PrPC-Aβ interactions could be crucial for AD-related impairment of synaptic plasticity (Lauren et al., 2009). In the present study, utilizing the Ca2+ probe aequorin targeted to different neuronal compartments we have measured Ca2+ fluxes in the plasma membrane, cytosol and the mitochondrial matrix of cerebellar granule neurons (CGN) derived from PrP-knockout (PrP-KO) mice and, as controls, from Tg46 mice in which normal PrPC levels were rescued over a PrP-KO genotype mice. We found that, compared to controls, PrP-KO neurons have significant increased Ca2+ transients in all the above domains after activating both store-operated Ca2+ channels (SOCC), glutamate and/or NMDA receptors (R) and that Aβ affects neuronal local Ca2+ fluxes in a PrPC-dependent way. Because of the involvement of p59Fyn and p42/p44 ERK (ERK 1/2) in regulating SOCC and the NMDA-R (Pozo-Guisado et al., 2010, Nakazawa et al., 2001), we then explored the possibility that PrPC modulates SOCC and the NMDA-R through p59Fyn and ERK 1/2 signaling pathways. We found that PrP-KO CGN had higher levels of active p59Fyn before activating both SOCC and NMDA-R and increased phosphorylated ERK1/2 only under the conditions that preceded NMDA-R activation. The difference of phosphorylated 59Fyn observed in untreated neurons before stimulating SOCC was abrogated by the presence of Aβ (1-42) fragments. These preliminary results indicate that p59Fyn and ERK 1/2 participate in the PrPC-dependent modulation of Ca2+ movements via SOCC and NMDA-R, and that PrPC-Aβ interactions increase SOCC-mediated Ca2+ transients by abolishing the PrPC-dependent downregulation of the p59Fyn pathway.