The Link of the Prion Protein with Ca²⁺ Metabolism and ROS Production, and the Possible Implication in Aβ Toxicity

• Main Authors: Agnese De Mario, Caterina Peggion, Maria Lina Massimino, Rosa Pia Norante, Alessandra Zulian, Alessandro Bertoli, Maria Catia Sorgato
• Format: Article
• Language: English
• Published: MDPI AG 2019-09-01
• Series: International Journal of Molecular Sciences
• Subjects: prion protein; Ca²⁺ homeostasis; glutamate; neurotransmission; synapses; ROS; Aβ oligomers; Fyn; NADPH oxidase
• Online Access: https://www.mdpi.com/1422-0067/20/18/4640

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 We will also illustrate and discuss past and unpublished results demonstrating that Aβ oligomers perturb Ca²⁺ homeostasis and cause abnormal mitochondrial accumulation of reactive oxygen species by possibly affecting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.