Critical Review Possible Role for Ca 21 in the pathophysiology of the prion protein? Caterina Peggion, 1 Alessandro Bertoli, 1 and M. Catia Sorgato 1,2 * 1 Department of Biological Chemistry, University of Padova, viale G. Colombo 3, 35131 Padova, Italy 2 CNR Institute of Neuroscience, University of Padova, viale G. Colombo 3, 35131 Padova, Italy Abstract. Transmissible spongiform encephalopathies, or prion diseases, are lethal neurodegenerative disorders caused by the infectious agent named prion, whose main constituent is an aberrant conformational isoform of the cellular prion protein, PrP C . The mechanisms of prion-associated neurodegeneration and the physiologic function of PrP C are still unclear, although it is now increasingly acknowledged that PrP C plays a role in cell differentiation and survival. PrP C thus exhibits dichotomic attributes, as it can switch from a benign function under normal conditions to the triggering of neuronal death during disease. By reviewing data from models of prion infection and PrP-knockout paradigms, here we discuss the possibility that Ca 2þ is the hidden factor behind the multifaceted behavior of PrP C . By featuring in almost all processes of cell signaling, Ca 2þ might explain diverse aspects of PrP C pathophysiology, including the recently proposed one in which PrP C acts as a mediator of synaptic degeneration in Alzheimer’s disease. V C 2011 International Union of Biochemistry and Molecular Biology, Inc. Volume 37, Number 3, May/June 2011, Pages 241–249  E-mail: catia.sorgato@unipd.it Keywords: prion disease, PrP C , Ca 21 homeostasis, Alzheimer’s disease 1. The prion protein and prion disease Transmissible spongiform encephalopathy (TSE), or prion disease, is a class of rare and fatal neurodegenerative disor- ders affecting humans and other mammalian species, which occurs on sporadic, genetic, or infectious grounds. Clinically, TSE presents with dementia, ataxia, and sometimes with psychiatric disturbances, while the histopathologic pattern of the brain typically shows vacuolation (from which the term ‘‘spongiform’’), extensive astrogliosis, and deposition of pro- tease-resistant aggregates. TSEs include Creutzfeldt-Jakob disease (CJD), Gerstmann-Stra¨ussler-Scheinker syndrome, fatal familial insomnia, and kuru in humans, scrapie in sheep, chronic wasting disease in cervids, and bovine spon- giform encephalopathy in cattle (better known as ‘‘mad cow disease’’) [1]. It is now established that these disorders occur when the cellular prion protein (PrP C ) undergoes a structural conversion into the aberrant ‘‘scrapie’’ conformer (PrP Sc ), thereby generating the protease-resistant core of TSE etiological agent, the prion [2]. Mammalian PrP C is a cell surface sialoglycoprotein of about 210 aminoacids, tethered to the plasma membrane by a glycosylphosphatidyl inositol moiety. The protein is expressed in almost all tissues, although it is particularly abundant in the central nervous system (CNS) and lymphoid organs. The nuclear magnetic resonance-resolved 3D struc- ture of mammalian recombinant PrPs has shown that the benign form of the protein invariably comprises a flexible, random coiled N-terminal domain and a globular, a-helix-rich C-terminal domain [3], as opposed to the remarkable increase in b structure typical of PrP Sc [4]. This conforma- tional switch imparts novel physico-chemical and biologic features to PrP Sc , including the propensity to generate amy- loid cross-b structures and the capacity to propagate into host organisms via a template-assisted process [4]. However, in spite of recent advancements in the understanding of the PrP C -to-PrP Sc structural conversion and the routes taken by exogenous prions to colonize the CNS, the present knowl- edge of both prion-related neurodegenerative processes and the physiologic function of PrP C remains poor. With respect to the cellular role of PrP C , its definition has been hampered by the absence of obvious phenotypes in mice carrying the ablation (also postnatal) of the PrP gene [5–7]. In fact, although PrP-knockout (KO) animals are immune to prion infection [8], they are developmentally normal and do not display neurodegenerative traits, except for mild neuro- physiologic and behavioral deficits [9,10]. This finding has raised the possibility that clear PrP-KO phenotypes would be detectable only under specific cell stress conditions that allow to bypass putative compensatory mechanisms. Accordingly, it has been demonstrated that PrP-KO mice show defective *Address for correspondence: M. Catia Sorgato, MS, Department of Biological Chemistry, University of Padova, Viale G. Colombo 3, 35131 Padova, Italy. Tel.: þ39 049 8276136; Fax: þ39 049 8073310; E-mail: catia.sorgato@unipd.it. Received 18 March 2011; accepted 23 March 2011 DOI: 10.1002/biof.161 Published online in Wiley Online Library (wileyonlinelibrary.com) 241