Understanding and exploiting interactions between cellular proteostasis pathways and infectious prion proteins for therapeutic benefit

Abstract

Several neurodegenerative diseases of humans and animals are caused by the misfolded prion protein (PrP^Sc), a self-propagating protein infectious agent that aggregates into oligomeric, fibrillar structures and leads to cell death by incompletely understood mechanisms. Work in multiple biological model systems, from simple baker's yeast to transgenic mouse lines, as well as in vitro studies, has illuminated molecular and cellular modifiers of prion disease. In this review, we focus on intersections between PrP and the proteostasis network, including unfolded protein stress response pathways and roles played by the powerful regulators of protein folding known as protein chaperones. We close with analysis of promising therapeutic avenues for treatment enabled by these studies.

Keywords: human; prions; protein chaperones; protein misfolding; stress; yeast.

Figure 1.

Prion templating and oligomerization is modulated by molecular chaperones. Soluble prion precursors (PrP^c, Sup35, Ure2) are recognized and converted by sub-stoichiometric prion forms of the same protein (PrP^sc, [PSI+], [URE3]) that template addition to growing oligomers (protofibrils). Fibrils grow by end addition and self-associate to become large aggregates/insoluble plaques. Protein chaperones (Hsp40/Hsp70) interact at multiple points in the prion generation pathway, including recognition of prion monomers, capping of growing ends to slow fibrillization and cleavage of fibrils back to shorter protofibrils that exponentially amplify deposit formation. Cleavage is mediated by either additional interaction of the disaggregase Hsp104 (in yeast) or the Hsp70-like Hsp110 that generates weak disaggregase activity in concert with Hsp40/Hsp70 (yeast and humans).

Figure 2.

Key unfolded protein stress response pathways in humans and yeast. The ER unfolded protein response (UPR) recognizes misfolded proteins within the ER lumen and membrane and activates downstream transcriptional responses to restore ER proteostasis. The yeast UPR is governed solely by Ire1, while humans possess three parallel pathways: IRE1, PERK and ATF6. The cytosolic heat shock response operates through Hsp70-mediated recognition of misfolded proteins in the cytoplasm and nucleoplasm and activates downstream gene expression through HSF1 to rebalance proteostasis in those compartments, as well as many ER-resident chaperones. Hsp70 chaperones play a common role in sensing and transducing the misfolded protein signal.

Figure 3.

[PSI+] prion biogenesis and chaperone interactions in yeast. The Sup35 protein is a critical translation termination factor in yeast that can be converted to the prion form [PSI⁺] via templated conversion. The yeast Hsp70/Hsp40 chaperone pair retards the conversion and formation of protofibrils. Fibrils can be disassembled via the action of either the Hsp104 disaggregase partnering with Hsp40/Hsp70, or the recently described chaperone triad disaggregase formed by Hsp70/Hsp40/Hsp110. Yeast protein names are shown in the figure and are further detailed in table 2. Small oligomers and [PSI⁺] monomers are capable of passing through the bud neck while larger fibrils are not, leading to [PSI⁺] curing in experimental models lacking disaggregase activity. Similar chaperone/prion dynamics are observed for [URE3].

Figure 4.

PrP-chaperone interactions during biogenesis. The cellular form of PrP is generated within the ER lumen and post-translationally modified by the addition of a GPI anchor (green dots). It is then transported through the secretory pathway (transparent arrow) for localization on the outer leaflet of the plasma membrane, where it exists in lipid raft sub-domains (yellow). Although it is unclear where precisely PrP^c to PrP^Sc (red dots) conversion occurs, available data are consistent with ER chaperones Grp58 (protein disulfide isomerase) and Grp78 (Hsp70; BiP) interacting with the PrP^Sc form within the lumen, targeting it for degradation through the ERAD pathway. This model does not exclude conversion at later points in the secretory pathway. PrP^Sc can also escape through the secretory pathway to localize to the plasma membrane and template conversion of PrP^c, ultimately adding to growing extracellular fibril chains.