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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 Ca²⁺ homeostasis. Indeed, by controlling gene expression and signaling cascades, PrP^C is able to optimize glutamate secretion and regulate Ca²⁺ entry via store-operated channels and ionotropic glutamate receptors, thereby protecting neurons from threatening Ca²⁺ overloads and excitotoxicity. We will also illustrate and discuss past and unpublished results demonstrating that Aβ oligomers perturb Ca²⁺ homeostasis and cause abnormal mitochondrial accumulation of reactive oxygen species by possibly affecting the PrP-dependent downregulation of Fyn kinase activity.