Prion neurotoxicity

Abstract

Although the mechanisms underlying prion propagation and infectivity are now well established, the processes accounting for prion toxicity and pathogenesis have remained mysterious. These processes are of enormous clinical relevance as they hold the key to identification of new molecular targets for therapeutic intervention. In this review, we will discuss two broad areas of investigation relevant to understanding prion neurotoxicity. The first is the use of in vitro experimental systems that model key events in prion pathogenesis. In this context, we will describe a hippocampal neuronal culture system we developed that reproduces the earliest pathological alterations in synaptic morphology and function in response to PrP Sc . This system has allowed us to define a core synaptotoxic signaling pathway involving the activation of NMDA and AMPA receptors, stimulation of p38 MAPK phosphorylation and collapse of the actin cytoskeleton in dendritic spines. The second area concerns a striking and unexpected phenomenon in which certain structural manipulations of the PrP C molecule itself, including introduction of N-terminal deletion mutations or binding of antibodies to C-terminal epitopes, unleash powerful toxic effects in cultured cells and transgenic mice. We will describe our studies of this phenomenon, which led to the recognition that it is related to the induction of large, abnormal ionic currents by the structurally altered PrP molecules. Our results suggest a model in which the flexible N-terminal domain of PrP C serves as a toxic effector which is regulated by intramolecular interactions with the globular C-terminal domain. Taken together, these two areas of study have provided important clues to underlying cellular and molecular mechanisms of prion neurotoxicity. Nevertheless, much remains to be done on this next frontier of prion science.

PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins

“…Prion diseases typically involve a long, silent period of PrP aggregation and propagation, and an explosive symptomatic phase which results from acute neurotoxicity [1,54,75]. While the mechanism(s) causing neuronal loss are not yet resolved it is clear that membrane-bound PrP C is required [12,48,58,65] and binding of misfolded PrP to PrP C is a critical step [11].…”

Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation

“…Given that the proteasome is involved in PrP Sc degradation [102,114,[120][121][122], it is conceivable that the massive overproduction of cytosolic N1 to some extent reduced the efficiency of the proteasome to degrade PrP Sc . And since activation of the MAP kinase p38 has been specifically linked to the toxic signaling underlying prion diseases [113,123,124], it seems likely that the increase in p38 phosphorylation in our TgN1 mice at terminal prion disease is a consequence of the elevated PrP Sc levels.…”

A New Take on Prion Protein Dynamics in Cellular Trafficking

“…Eventually, failures in the processing of PrP C might lead to the aggregation and accumulation of misfolded prion proteins in the cytoplasm and a posterior advance of PrP Sc agents (here, PrP Sc or prion refers to disease-associated infectious form) to other cells [ 44 ]. PrP Sc is capable of catalyzing the conversion of PrP C to the infectious isoform ( Figure 2 ), and it displays neurotoxic features, such as the capacity of accumulating in the brain [ 84 ] and, causing synaptic dysfunctions [ 85 , 86 ]. Pathological prion is related to the neurodegenerative effects of TSEs and also to the loss-of-function of physiological PrP C [ 3 ].…”