Prion strains viewed through the lens of cryo-EM

Abstract

Mammalian prions are lethal transmissible pathogens that cause fatal neurodegenerative diseases in humans and animals. They consist of fibrils of misfolded, host-encoded prion protein (PrP) which propagate through templated protein polymerisation. Prion strains produce distinct clinicopathological phenotypes in the same host and appear to be encoded by distinct misfolded PrP conformations and assembly states. Despite fundamental advances in our understanding of prion biology, key knowledge gaps remain. These include precise delineation of prion replication mechanisms, detailed explanation of the molecular basis of prion strains and inter-species transmission barriers, and the structural definition of neurotoxic PrP species. Central to addressing these questions is the determination of prion structure. While high-resolution definition of ex vivo prion fibrils once seemed unlikely, recent advances in cryo-electron microscopy (cryo-EM) and computational methods for 3D reconstruction of amyloids have now made this possible. Recently, near-atomic resolution structures of highly infectious, ex vivo prion fibrils from hamster 263K and mouse RML prion strains were reported. The fibrils have a comparable parallel in-register intermolecular β-sheet (PIRIBS) architecture that now provides a structural foundation for understanding prion strain diversity in mammals. Here, we review these new findings and discuss directions for future research.

Strain‐dependent role of copper in prion disease through binding to histidine residues in the N‐terminal domain of prion protein

“…Strain‐dependent prion susceptibility has been explained by the strain‐dependent conversion of PrP C into PrP Sc . PrP Sc molecules from different strains have been demonstrated to adopt different conformations (Artikis et al, 2022; Hoyt, Alam, et al, 2022; Hoyt, Standke, et al, 2022; Kraus et al, 2021; Manka, Wenborn, Betts, et al, 2023; Manka, Wenborn, Collinge, & Wadsworth, 2023). RML‐PrP Sc has a major PK cleavage site around residue 90, whereas BSE‐PrP Sc is cleaved between His95 and the asparagine at codon 96 (Hayashi et al, 2005; Mange et al, 2004), suggesting different conformations between RML‐ and BSE‐PrP Sc s. The conformational compatibility between PrP C and PrP Sc is an important factor in determining the conversion efficiency of PrP C into PrP Sc .…”

“…Prion diseases are a group of devastating neurodegenerative disorders, including Creutzfeldt‐Jakob disease in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals (Aguzzi et al, 2008; Artikis et al, 2022; Collinge, 2016; Manka, Wenborn, Collinge, & Wadsworth, 2023; Prusiner, 1998). The causative agents are proteinaceous infectious particles, the so‐called prions, which are widely believed to consist, if not entirely, of the abnormally folded amyloidogenic isoform of the prion protein PrP Sc (Aguzzi et al, 2008; Artikis et al, 2022; Collinge, 2016; Manka, Wenborn, Collinge, & Wadsworth, 2023; Prusiner, 1998). PrP Sc is produced through the conformational conversion of the cellular isoform of the prion protein, PrP C , a membrane glycoprotein that is most abundantly expressed in the brain, particularly in neurons (Artikis et al, 2022; Collinge, 2016; Manka, Wenborn, Collinge, & Wadsworth, 2023).…”

“…The causative agents are proteinaceous infectious particles, the so‐called prions, which are widely believed to consist, if not entirely, of the abnormally folded amyloidogenic isoform of the prion protein PrP Sc (Aguzzi et al, 2008; Artikis et al, 2022; Collinge, 2016; Manka, Wenborn, Collinge, & Wadsworth, 2023; Prusiner, 1998). PrP Sc is produced through the conformational conversion of the cellular isoform of the prion protein, PrP C , a membrane glycoprotein that is most abundantly expressed in the brain, particularly in neurons (Artikis et al, 2022; Collinge, 2016; Manka, Wenborn, Collinge, & Wadsworth, 2023). We and others have shown that mice devoid of PrP C ( Prnp 0/0 ) are resistant to prion infections and neither propagate PrP Sc or prions in their brains nor develop disease, even after intracerebral inoculation with prions (Bueler et al, 1993; Manson et al, 1994; Prusiner et al, 1993; Sakaguchi et al, 1995), confirming that the conversion of PrP C to PrP Sc is a key pathogenic event in prion diseases.…”

New developments in prion disease research

“…Recently, near-atomic resolution structures of different prion strains were reported from various groups. The review by Wadsworth and colleagues discusses their parallel in-register intermolecular β-sheet (PIRIBS) architectures and how this provides a structural foundation for understanding prion strain diversity (Manka et al 2022). Finally, the review by David Westaway and collages addresses prion-like mechanisms in tauopathies, which are associated with a wide spectrum of clinicopathologically diverse neurodegenerative diseases.…”

Deficiency in ST6GAL1, one of the two α2,6-sialyltransferases, has only a minor effect on the pathogenesis of prion disease

“…The diversity of disease phenotypes within the same host has been attributed to the ability of PrP C to acquire multiple, structurally distinct, self-replicating PrP Sc states referred to as prion strains ( Bessen and Marsh, 1992 ; Safar et al, 1998 ; Peretz et al, 2001 ; Ayers et al, 2011 ; Gonzalez-Montalban et al, 2011 ; Klimova et al, 2015 ; Morales et al, 2016 ). The fact that prion strains are structurally different has been well documented ( Caughey et al, 2022 ; Manka et al, 2022 ), yet how prion strains elicit multiple, strain-specific disease phenotypes has not been answered ( Baskakov, 2021 ).…”