The Link of the Prion Protein with Ca(2+) Metabolism and ROS Production, and the Possible Implication in Aβ Toxicity

The cellular prion protein (PrP(C)) is an ubiquitous cell surface protein mostly expressed in neurons, where it localizes to both pre- and post-synaptic membranes. PrP(C) aberrant conformers are the major components of mammalian prions, the infectious agents responsible for incurable neurodegenerative disorders. PrP(C) was also proposed to bind aggregated misfolded proteins/peptides, and to mediate their neurotoxic signal. In spite of long-lasting research, a general consensus on the precise pathophysiologic mechanisms of PrP(C) has not yet been reached. Here we review our recent data, obtained by comparing primary neurons from PrP-expressing and PrP-knockout mice, indicating a central role of PrP(C) in synaptic transmission and Ca(2+) homeostasis. Indeed, by controlling gene expression and signaling cascades, PrP(C) is able to optimize glutamate secretion and regulate Ca(2+) entry via store-operated channels and ionotropic glutamate receptors, thereby protecting neurons from threatening Ca(2+) overloads and excitotoxicity. We will also illustrate and discuss past and unpublished results demonstrating that Aβ oligomers perturb Ca(2+) homeostasis and cause abnormal mitochondrial accumulation of reactive oxygen species by possibly affecting the PrP-dependent downregulation of Fyn kinase activity.