What Is Our Current Understanding of PrPSc-Associated Neurotoxicity and Its Molecular Underpinnings?

Abstract

The prion diseases are a collection of fatal, transmissible neurodegenerative diseases that cause rapid onset dementia and ultimately death. Uniquely, the infectious agent is a misfolded form of the endogenous cellular prion protein, termed PrP^Sc. Despite the identity of the molecular agent remaining the same, PrP^Sc can cause a range of diseases with hereditary, spontaneous or iatrogenic aetiologies. However, the link between PrP^Sc and toxicity is complex, with subclinical cases of prion disease discovered, and prion neurodegeneration without obvious PrP^Sc deposition. The toxic mechanisms by which PrP^Sc causes the extensive neuropathology are still poorly understood, although recent advances are beginning to unravel the molecular underpinnings, including oxidative stress, disruption of proteostasis and induction of the unfolded protein response. This review will discuss the diseases caused by PrP^Sc toxicity, the nature of the toxicity of PrP^Sc, and our current understanding of the downstream toxic signaling events triggered by the presence of PrP^Sc.

Keywords: PrPSc; neurodegeneration; neurotoxicity; prion disease; proteostasis.

Figure 1

The conversion of PrP^C to PrP^Sc. The protein only hypothesis of prion conversion posits that misfolded PrP^Sc acts a catalyst, directly binding to PrP^C and causing its conversion to PrP^Sc. This self-perpetuating recruitment leads to large aggregates of PrP^Sc, and underlies its infectious potential. Surprisingly, aggregated PrP^Sc appears to be minimally toxic, with smaller, soluble oligomers of PrP^Sc likely mediating the majority of the observed neurodegeneration. Importantly, PrP^C is required for both the conversion process and for the toxicity of PrP^Sc to manifest.

Figure 2

The neuropathology of prion disease. (A). The Rocky Mountain Laboratory (RML) strain of prion disease induces extensive neurodegeneration in mice, especially in the hippocampus where considerable neuronal death is observed in the CA1 region (hematoxylin and eosin stained hippocampal sections from uninfected control mice, or prion-infected terminal tg37^+/− mice) (B). Prion infection is associated with the accumulation of PrP^Sc, which is often detected by its partial proteinase resistance to digestion by proteinase K (total PrP and PrP^Sc levels, detected with and without proteinase K digestion) (C). Spongiosis, an intracellular oedema that appears as holes in histological slices after fixation, is observed throughout the brain in both human and animal cases of prion disease (hematoxylin and eosin stained hippocampal sections from uninfected control mice, or prion-infected terminal tg37^+/− mice).

Figure 3

Disruption of the ubiquitin proteasome system by PrP^Sc. PrP^Sc can directly inhibit the 26S proteasome by binding to the 20S subunit, preventing substrate entry. The causes increased PrP^Sc aggregation and accumulation of poly-ubiquitinated proteins in the cytoplasm.

Figure 4

The role of the unfolded protein response (UPR) in prion neurodegeneration. Aggregates of PrP^Sc activate PERK signaling, leading to a reduction in protein synthesis rates mediated by the phosphorylation of eIF2α. This starves neurons of essential proteins, leading to neurodegeneration. Restoring translation rates via lentiviral expression of GADD34 or treatment with a variety of small molecule inhibitors increases translation and is substantially neuroprotective.