Role of Lipid Rafts in PrP50 Formation

Like other pathogens, infectious prions might use rafts to enter the cells and possibly to initiate and propagate the PrPc to PrPSc conversion process that allows prion amplification [56,66-68]. Several lines of evidences suggest that rafts are candidate sites for the generation of PrPSc in infected cells:

• Both PrPc and PrPSc are recovered in lipid rafts [68].

• Impairment of raft association by drugs that reduce intracellular levels of cholesterol decrease PrPSc formation in infected cells [33]; similarly, removal of PrPc from rafts by exchanging its GPI anchor with a transmembrane domain prevents PrPSc formation [63].

• Infectious prion rods were found to contain two sphingolipids, GalCer and sphingomyelin [69], which are enriched in rafts, suggesting that selected raft lipids might interact with normal and/or pathogenic prion proteins. In particular, PrPc and PrPSc-associated rafts appear to have different characteristics, being separated from each other by solubilization and flotation on density gradients [68].

These data suggest either the presence of different kinds of rafts or different characteristics of membrane association of the wild-type and pathological isoforms with the same raft-type. The exact mechanisms by which rafts could control the transconformation of PrPc to PrPSc remains unknown, although different scenarios can be envisaged [26]:

1. Rafts could function as a platform by which PrPc is transported to a specific compartment where the conformational change into PrPSc occurs (Fig. 10.1A). We have shown previously that in transfected cells, cholesterol- and sphingo-lipid-depleting drugs which impair PrPc raft association do not impair its exo-cytic trafficking to the plasma membrane [70], but rather slow down PrPc endo-cytic trafficking (D. Sarnataro, personal communication), suggesting that rafts could represent the cellular environment that regulates PrPSc biosynthesis during endocytosis.

2. Rafts might represent a container of indispensable machinery required for PrPSc formation, such as proteins/lipids, that facilitate the conversion process (Fig. 10.1B).

3. Rafts could represent a favorable environment for transconformation by facilitating a close encounter between the substrate (PrPc) and the seed (PrPSc), and could act by concentrating PrPc and PrPSc molecules within confined regions of the plasma membrane (Fig. 10.1C). The role of rafts as a "meeting place" between PrPc and PrPSc is supported by the studies of Baron et al., who have shown that PrPc to PrPSc transconformation occurs only when the two protagonists of the reaction are inserted into contiguous membranes [32].

4. Rafts might allow a direct interaction of sphingolipids and/or cholesterol with PrPc and/or with PrPSc, which could affect the conformational stability of PrPC (Fig. 10.1D). In this case, it is possible that different raft-resident lipids could act as molecular chaperones to facilitate the unfolding of one or more a-helices or the refolding into b-sheets of PrPc. Alternatively, a change in the local environment (in terms of enrichment in specific lipids and proteins) could mediate this process.

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