What is the role of lipids in prion conversion and disease?

Abstract

The molecular cause of transmissible spongiform encephalopathies (TSEs) involves the conversion of the cellular prion protein (PrP^C) into its pathogenic form, called prion scrapie (PrP^Sc), which is prone to the formation of amorphous and amyloid aggregates found in TSE patients. Although the mechanisms of conversion of PrP^C into PrP^Sc are not entirely understood, two key points are currently accepted: (i) PrP^Sc acts as a seed for the recruitment of native PrP^C, inducing the latter's conversion to PrP^Sc; and (ii) other biomolecules, such as DNA, RNA, or lipids, can act as cofactors, mediating the conversion from PrP^C to PrP^Sc. Interestingly, PrP^C is anchored by a glycosylphosphatidylinositol molecule in the outer cell membrane. Therefore, interactions with lipid membranes or alterations in the membranes themselves have been widely investigated as possible factors for conversion. Alone or in combination with RNA molecules, lipids can induce the formation of PrP in vitro-produced aggregates capable of infecting animal models. Here, we discuss the role of lipids in prion conversion and infectivity, highlighting the structural and cytotoxic aspects of lipid-prion interactions. Strikingly, disorders like Alzheimer's and Parkinson's disease also seem to be caused by changes in protein structure and share pathogenic mechanisms with TSEs. Thus, we posit that comprehending the process of PrP conversion is relevant to understanding critical events involved in a variety of neurodegenerative disorders and will contribute to developing future therapeutic strategies for these devastating conditions.

Keywords: aggregation; neurodegenerative disease; prion diseases; prion protein; protein-lipid interaction.

Figure 1

The physiological effects of PrP interaction with membrane lipids. Location on lipid rafts enables PrP^C interaction with various ligands, including membrane lipids. (A) Cellular starvation can alter the plasma membrane order, leading to PS exposure to the extracellular medium and increased PA. The interaction of N1 and N2 fragments, peptides derived from the proteolytic cleavage of PrP, may have a regulatory effect on cellular stress by binding to PS and PA. The interaction of N1 and N2 with PA can activate the Ras–MEK–ERK pathway and promote cell survival. At the same time, the interaction with PS can also activate pathways related to the same function. (B) PrP^C is formed in the endoplasmic reticulum, which undergoes post-translational modifications, such as binding to the GPI anchor. Subsequently, it is taken to the Golgi complex (1) and forwarded to the plasma membrane (2), mainly in lipid rafts (3). The importance of cholesterol in lipid rafts for the physiological location of PrP^C has already been reported. The process of internalization of PrP requires a lateral movement (4) to areas where the membrane is more soluble, outside the lipid rafts. Endosome motility is related to the function of Rab proteins, such as Rab 5 for early endosomes (5), Rab 7 for the multivesicular body (MVB)/late endosomes (6), and Rab11 for the endosomal recycling compartment (ERC) (green arrows). Conversion of PrP^C to PrP^Sc can occur within ERC and MVBs. MVBs fuse to lysosomes (7) and proteins are degraded in endolysosomes (8). The cleavage of PrP^C from the GPI anchor may favor PrP-lipid interaction and PrP conversion, but cells expressing PrP without GPI are not infected. Drugs that sequester cholesterol are raft dissociation drugs (RDD), known to inhibit PrP^Sc formation. (C) The interaction of GM1 ganglioside and N1 fragment promotes the increase of GM1 in the plasma membrane. It stimulates the secretion of the cytokine CxCl10, enabling the interaction between microglia and other surrounding cells. The interaction between PrP^C and GM1 has been reported, but the mechanisms triggered by this interaction have not been elucidated but are possibly related to cell signaling and cell recognition process. (D) PrP^C binds to copper ions and is involved in ion metabolism. It has already been reported that the interaction between copper and PrP^C stimulates the endocytosis of PrP. In the presence of copper, PrP^C leaves the lipid raft region and internalizes mainly via clathrin-mediated endocytosis, balancing the amount of copper inside and outside the cell. Created with BioRender.com.

Figure 2

PrP^C interaction with lipids in pathology (A) Glycerophospholipids are proposed as potential biomarkers for TSEs as their concentration increases in prion disease models. The interaction of PrP with POPG can modulate the formation of proteinase K-resistant PrP^Sc aggregates. (B) It has already been reported that the presence of PrP^Sc increases free cholesterol and activates cell death mechanisms by activating phospholipase A (PLA). (C) The presence of sphingolipids in the membrane is essential in inhibiting the presence of PrP^Sc. Depletion of sphingolipids SM and GM1, using the ceramide synthase inhibitor fumonisin B(1), has been reported to increase the presence of PrP^Sc in neuroblastoma cells infected with PrP^Sc. (D) The presence of PrP^Sc in the plasma membrane prevents the internalization of copper, promoting a series of harmful consequences to the cell, mainly related to oxidative stress. Created with BioRender.com.

Figure 3

Lipid-mediated PrP^C conversion and aggregation in vitro. In vitro studies show lipid vesicle interaction with PrP^C, leading to PrP^Sc formation. Examples of glycerophospholipids are POPG, PE, PA, and others. Once formed, PrP^Sc converts more PrP^C to the pathological form, initiating an aggregation process that may culminate in the shape of PrP^Sc oligomers and PrP^Sc fibrils. Created with BioRender.com.