Prion protein biosynthesis and its emerging role in neurodegeneration

Abstract

Various fatal neurodegenerative disorders are caused by altered metabolism of the prion protein (PrP). These diseases are typically transmissible by an unusual 'protein-only' mechanism in which a misfolded isomer, PrP(Sc), confers its aberrant conformation onto normal cellular PrP. An impressive range of studies has investigated nearly every aspect of this fascinating event; yet, our understanding of how PrP(Sc) accumulation might lead to cellular dysfunction and neurodegeneration is trifling. Recent advances in our understanding of normal PrP biosynthesis and degradation might have unexpectedly shed new light on this complex problem. Indeed, our current understanding of normal PrP cell biology, coupled with a growing appreciation of its complex metabolism, is providing new hypotheses for PrP-mediated neurodegeneration.

Figure 1

Overview of PrP^C and PrP^Sc metabolism. Nascent PrP (green line) is synthesized at the ER and imported into the ER lumen, where it is processed and folded into its final conformation (green triangle). Properly folded PrP is trafficked through the Golgi to the cell surface. Cell-surface PrP^C recycles through endosomes, eventually being degraded in lysosomes with a half-life of ~3–6 h. The lower right shows the consequences of extrinsic PrP^Sc (red square). PrP^C and PrP^Sc can interact, and both can be internalized into endosomes. Although the location is poorly defined, PrP^Sc converts PrP^C into additional PrP^Sc. Because PrP^Sc has a longer half-life (~24 h) for lysosomal degradation, it can accumulate to relatively high levels in intracellular compartments of the endo-lysosomal system.

Figure 2

Summary of the co-translational targeting and translocation of PrP into the ER, highlighting key steps that lead to the generation of its multiple isoforms. (a) Line diagram of PrP showing the location of its N-terminal signal sequence (blue), central hydrophobic domain (HD; black) and C-terminal GPI-anchoring sequence (red). (b) Important steps in PrP translocation taken by the majority (~80%) of molecules. As the N-terminal signal sequence emerges from the ribosome, it is recognized by the signal recognition particle (SRP) and targeted to the Sec61 translocon. The signal sequence then interacts with Sec61 and, with the aid of accessory factors such as TRAM and TRAP, gates open the Sec61 channel to initiate translocation. Forward transport into the lumen (or prevention of slippage back to the cytosol) might require chaperones. Sites of known or potential inefficiency of the signal sequence that lead to slipping of the N terminus into the cytosol are indicated by red asterisks. During translocation in vitro, some PrP molecules insert into the membrane to generate ^NtmPrP, a poorly studied form of which the relevance or existence in vivo remains to be studied. CHO denotes N-linked glycans. (c) Consequences of signal inefficiency. The ellipsis in place of the signal sequence indicates that both signal-containing and signal-cleaved molecules can be generated, depending on the precise step at which PrP slipped in part (b). Engagement of the translocon by the HD generates ^CtmPrP, whereas lack of engagement results in cyPrP. ^CtmPrP is typically a minor species, but it can be increased by mutations that raise HD hydrophobicity. Shown below each PrP species are their relative amounts thought to be generated in cells (not necessarily their steady state levels). Lysosomal degradation is presumed but has not been experimentally demonstrated yet.

Figure 3

Speculative working model of prion disease pathogenesis. Templated replication of PrP^Sc from PrP^C leads to PrP^Sc accumulation. This has several indirect consequences for cellular function, three of which are indicated. The effect of each consequence on nascent PrP metabolism is listed, along with the net result of increased cyPrP and ^CtmPrP, which are both capable of causing neurodegeneration.