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

Agnese De Mario,Rosa Pia Norante,Maria Catia Sorgato,Alessandro Bertoli,Maria Lina Massimino,Caterina Peggion,Alessandra Zulian

doi:10.3390/ijms20184640

Abstract

The cellular prion protein (PrPC) is an ubiquitous cell surface protein mostly expressed in neurons, where it localizes to both pre- and post-synaptic membranes. PrPC aberrant conformers are the major components of mammalian prions, the infectious agents responsible for incurable neurodegenerative disorders. PrPC 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 PrPC 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 PrPC in synaptic transmission and Ca2+ homeostasis. Indeed, by controlling gene expression and signaling cascades, PrPC 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 We will also illustrate and discuss past and unpublished results demonstrating that Aβ oligomers perturb Ca2+ homeostasis and cause abnormal mitochondrial accumulation of reactive oxygen species by possibly affecting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.

Highlights

Nowadays, neurodegenerative disorders affecting elderly people is one major health problem worldwide, which is aggravated by lack of early diagnostic tools and pharmaceutical approaches
Mass spectrometry was used to quantify glutamate release from depolarized primary cerebellar granule neurons (CGN) expressing, or not (PrP-KO), the protein; immunolabeling approaches to follow synaptic vesicle recycling; quantitative mass spectrometry, flanked by selected reaction monitoring and qRT-PCR for data validation, to determining the protein expression profile in the two neuronal types. These analyses clearly demonstrated that glutamate release and synaptic vesicle dynamics are profoundly compromised in PrP-KO CGN, a result that could be attributed to the underrepresentation of proteins that, among others, are key actors in the two processes—i.e., Rab 3a, syntaxin 1b, and synaptogyrin 3—that are involved in neurotransmitter release, and other three Rab isoforms playing a role in vesicular trafficking
To decipher other aspects of PrPC operational modes at synapses, we considered past reports on the impact of the protein on Ca2+-dependent pathways, and their deviation in prion and PrP-KO paradigms, and the ambivalent nature shared by PrPC and Ca2+

Summary

Introduction

Neurodegenerative disorders affecting elderly people is one major health problem worldwide, which is aggravated by lack of early diagnostic tools and pharmaceutical approaches. Despite its much less occurrence (1–2 cases per million), prion disorders have become renown after appearance of mad cow disease [1], and the development in man of a variant form of the Creutzfeldt–Jakob disease [2] caused by ingestion of bovine prion-tainted food. All these disorders may have a genetic origin, which, accounts for only a few percentages of cases. PrPC Supports Correct Neuronal Activities by Regulating Gene Expression and Ca2+ Metabolism

Action of PrPC at Pre-Synapses

Action of PrPC on SOCE and iGluRs

Effects of Aβ Oligomers on PrPC-Linked Neuronal Controls

Findings

Conclusions