Possible role for Ca2+ in the pathophysiology of the prion protein?

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(2+) is the hidden factor behind the multifaceted behavior of PrP(C) . By featuring in almost all processes of cell signaling, Ca(2+) 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.

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

“…Lastly, transcripts for three physiologically cytoprotective proteins also known for their potential to induce neurodegenerative diseases when misfolded, were upregulated by TRO40303: prion protein (Prnp), amyloid beta (A4) precursor protein (App) and endogenous mouse-alpha-synuclein (Snca). Whereas the misfolded form of prion protein is neurotoxic, the properly folded prion protein has neuroprotective properties attributed to a decrease in calcium overload in response to different cell stressors, an effect that has also been seen after exposure of cells to TRO40303 (Peggion et al, 2011; Schaller et al, 2010). Similar to App (Corrigan et al, 2011) and Prnp, wildtype Snca is protective to nerve terminals due to its physiological role in synaptic function (Chandra et al, 2005).…”

Early Mechanisms of Pathobiology Are Revealed by Transcriptional Temporal Dynamics in Hippocampal CA1 Neurons of Prion Infected Mice

“…Cellular PrP protein may even have a major direct role in Ca 2+ homeostasis (for review, see [100]). This could occur via two means: PrP C misfolding during disease interrupts Ca 2+ homeostasis or PrP Res oligomerization forms pores in cell membranes which are permeable to ions.…”

Genetic variability of the gene cluster CALHM1–3 in sporadic Creutzfeldt-Jakob disease

“…Perturbations of calcium regulation has been described in several neurodegenerative disorders, such as Alzheimer (AD), amyotrophic lateral sclerosis, Parkinson, Huntington and prion diseases. [1][2][3][4][5][6][7][8][9][10][11] In 2008, Dreses-Werringloer and collaborators identified a polymorphism (rs2986017) associated with AD in the gene CALHM1 coding for a novel regulator of calcium homeostasis called CALHM1, which appears to be involved in the metabolism of amyloid β precursor protein (APP). 12 Although some authors have failed to confirm these results, a meta-analysis has shown that this polymorphism modulates the age at disease onset.…”