Prion protein and prion disease at a glance

The term ‘prion’ was first coined by Stanley Prusiner in 1982 to describe the ‘proteinaceous infectious particles’ that lead to a variety of fatal and transmissible neurodegenerative diseases, including scrapie, Creutzfeldt–Jakob disease (CJD) and kuru (Prusiner, 1982). Their mechanism of action was reminiscent of that described by John Griffith in the ‘protein-only’ hypothesis outlined in 1967, claiming the existence of self-replicating proteins responsible for scrapie (Griffith, 1967). A unique protein, designated prion protein (PrP), was purified from scrapie-infected hamster brain that showed resistance to limited proteinase K digestion (Bolton et al., 1982; McKinley et al., 1983; Prusiner et al., 1982, 1983). Notably, the concentration of PrP was proportional to the titer of the infectious prion, suggesting that PrP represents the major component of prion. Based on partial sequences of PrP (Prusiner et al., 1984), a gene encoding this protein was cloned in both scrapie-infected and uninfected animals (Oesch et al., 1985). The unexpected finding that PrP is encoded by the host genome suggested that prion consists of a modified pathological form of a normal cellular protein. The normal cellular prion protein (PrP^C) and pathological scrapie prion protein (PrP^Sc) share the same amino acid sequences, but differ mainly in their conformation and associated biochemical properties, such as proteinase resistance and solubility (Barry et al., 1986; Basler et al., 1986; Meyer et al., 1986) (see poster). It is now well recognized that the conformational transition from PrP^C to PrP^Sc represents a central molecular event during prion disease. As the main component of prion, PrP^Sc serves as a template to accrete and transform PrP^C into nascent PrP^Sc, followed by the fragmentation of the PrP^Sc aggregates into infectious propagons to recruit further PrP^C, thereby promoting prion replication and propagation (Aguzzi and Zhu, 2017; Ayers et al., 2020; Baral et al., 2019).

Prion diseases include scrapie in sheep and goat, bovine spongiform encephalopathy (BSE, also called mad cow disease) in cattle, chronic wasting disease (CWD) in cervids, transmissible mink encephalopathy (TME) in minks, feline spongiform encephalopathy (FSE) in felines and camel prion disease (CPD) in dromedary camels (Li et al., 2021b). In human, the most prevalent prion disease is sporadic Creutzfeldt–Jakob disease (sCJD), with other prion diseases including inherited CJD, iatrogenic CJD, variant CJD, Gerstmann–Sträussler–Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru (Aguzzi et al., 2013; Aguzzi and Zhu, 2012; Scheckel and Aguzzi, 2018). Although the etiology of prion diseases can be sporadic, inherited or acquired by iatrogenic or dietary exposure, they share similar neuropathological characteristics comprising spongiform changes, neuronal loss, astrogliosis and microglial activation, accompanied by the deposition of PrP^Sc aggregates in the brain (Aguzzi et al., 2013; Scheckel and Aguzzi, 2018; Sigurdson et al., 2019). Owing to the transmissibility of prions and typical spongiform changes in the prion-diseased brains, prion diseases are also called transmissible spongiform encephalopathies (TSE). In this Cell Science at a Glance article and the accompanying poster, we discuss recent progresses on the structural characterization and physiological function of prion protein, the cellular and molecular mediators of prion pathogenesis, the expanding prion concept and the involvement of prion protein in other neurodegenerative diseases, followed by highlighting the latest advances on the diagnosis and therapeutics of prion diseases.

PrP^C is a constitutively expressed glycoprotein that is bound to the cell plasma membrane by a glycosylinositol phospholipid anchor (GPI) (Stahl et al., 1987). Prion protein can adopt distinct structures. Secondary structure analysis by Fourier transform infrared (FTIR) and circular dichroism (CD) showed that PrP^Sc is predominantly composed of β-sheets, whereas PrP^C contains a high proportion of α-helices (Caughey et al., 1991; Gasset et al., 1993; Pan et al., 1993; Safar et al., 1993). More detailed structural characterization of recombinant murine PrP^C by nuclear magnetic resonance (NMR) revealed that it contains an unstructured N-terminal flexible tail and a globular C-terminal domain comprising a two-stranded antiparallel β-sheet and three α-helixes (Riek et al., 1996, 1997). A similar structure of human PrP^C was determined by X-ray crystallography (Knaus et al., 2001) (see poster). Nevertheless, the high-resolution structure of PrP^Sc remains elusive, largely due to the insolubility and heterogeneity of the purified infectious agents. Moreover, the existence of the different PrP^Sc conformations by which prion strains are defined adds another challenge (Collinge and Clarke, 2007; Soto and Pritzkow, 2018). Elucidating PrP^Sc structure will not only help to understand the mechanisms of prion replication and the molecular basis of prion strain phenomenon, but also provide fundamental knowledge for drug design and development to combat prion diseases.

Based on low-resolution structural data, several theoretical molecular models of PrP^Sc structure have been proposed, such as a spiraling protofibril (DeMarco and Daggett, 2004), left-handed β-helix (Govaerts et al., 2004) and parallel in-register β-sheet (Cobb et al., 2007; Smirnovas et al., 2011). Each proposed model fits some but not all experimental data; therefore, which model represents the bona fide PrP^Sc structure remains contentious. Recently, X-ray fiber-diffraction of infectious prion from hamster brains and cryo-electron microscopy (cyro-EM) of purified infectious GPI-anchorless prion fibrils from mouse brains has suggested that prion consists of stacks of four-rung β-solenoids (Vazquez-Fernandez et al., 2016; Wille et al., 2009). This finding is compatible with the left-handed β-helix model (Govaerts et al., 2004), although the resolution was insufficient to display atomic details of the structure. However, an atomistic model of prion structure has been constructed to simulate the conversion of PrP^C conversion into PrP^Sc (Spagnolli et al., 2019) (see poster). More recent cryo-EM of two different domains of recombinant human prion fibril has revealed that the fibril consists of two protofibrils intertwined in a left-handed helix, which is partly compatible with the four-rung β-solenoid (Glynn et al., 2020; Wang et al., 2020). Since the structures of in vitro generated recombinant PrP fibrils and brain-derived infectious PrP^Sc can differ significantly (Wille et al., 2009), the atomic structure of tissue-isolated pathogenic prions remains to be deciphered. Furthermore, how these structural differences relate to the varying infectivity requires more investigation. Additionally, we still do not know whether these structural models reflect real structures of various mutated PrP (especially the truncated mutations 145X and 163X) in genetic prion disease and how these models explain the strong effect of polymorphism (methionine versus valine) at codon 129 of the PrP on disease phenotype.

Although prion protein is highly conserved among mammals, animals lacking PrP^C develop and behave normally (Benestad et al., 2012; Bueler et al., 1992; Richt et al., 2007; Yu et al., 2009; Zhu et al., 2009). Several Prnp-knockout mouse lines have been established (Table 1) (Bueler et al., 1992; Heikenwalder et al., 2008; Manson et al., 1994; Moore et al., 1999; Nuvolone et al., 2016; Rossi et al., 2001; Sakaguchi et al., 1996; Yokoyama et al., 2001). Detailed analysis of Prnp-knockout mice attribute various physiological functions to PrP^C, including synaptic transmission, memory, sleep and neurite outgrowth, among others (Watts et al., 2018; Wulf et al., 2017). Nevertheless, controversial results have been reported due to the limitations of animal models used. In 1992, the first and most widely studied Prnp-knockout mouse line was established with a mixed background (129/Sv×C57BL/6) (Bueler et al., 1992). Although repeated backcrossing to C57BL/6 produced a congenic Prnp-knockout line, a small portion of the chromosome surrounding the targeted Prnp locus is still derived from the 129 strain (Bueler et al., 1992). This finding raises the question of whether any observed phenotypes were caused by the polymorphisms in the genes flanking Prnp. Indeed, an early observation that the inhibition of phagocytosis of apoptotic cells by Prnp^−/− macrophages was due to the polymorphism of Sipra, a flanking gene that co-segregated with the targeted Prnp from the 129 strain (Nuvolone et al., 2013). To overcome this pitfall, a co-isogenic Prnp-knockout line Prnp^Edbg has been established by gene targeting on 129/Ola embryonic stem cells (ESCs) and maintaining the line in 129/Ola genetic background (Manson et al., 1994). However, the 129/Ola background restricts its wide application. Recently, a new co-isogenic Prnp-knockout mouse line with a pure C57BL/6J genetic background was established by using transcription activator-like effector nuclease (TALEN)-mediated genome editing, a technology that enables direct gene targeting on a pure C57BL/6J strain and bypasses using 129/Sv-derived ESCs (Nuvolone et al., 2016). This new line is allowing experiments to prove or disprove the previously observed phenotypes and to determine the exact function of PrP^C (Henzi and Aguzzi, 2021; Henzi et al., 2020; Nuvolone et al., 2016).

Among the few widely accepted physiological functions, the involvement of PrP^C in the maintenance of peripheral myelination in mice has been well established. Upon amino-proximal cleavage, the released N-terminal polycationic cluster of PrP^C binds to the G-protein-coupled receptor Adgrg6 (also known as Gpr126) on Schwann cells, where it elicits a cyclic AMP (cAMP) response to promote myelination (Bremer et al., 2010; Kuffer et al., 2016) (see poster). This bona fide function of PrP^C is conserved in goat, since goat, which naturally lacks PrP^C, also develop peripheral demyelinating polyneuropathy upon aging (Skedsmo et al., 2020).

The molecular mechanisms underlying prion-induced neurodegeneration remain largely unknown. In mouse models of prion infection, PrP^Sc accumulation causes sustained overactivation of a branch of unfolded protein response (UPR), resulting in phosphorylation of the protein kinase-like ER kinase (PERK; also known as EIF2AK3). Phosphorylated (p-)PERK could in turn phosphorylate eIF2α, which blocks the initiation of translation and synthesis of new protein, eventually leading to synaptic failure and neuronal loss (Moreno et al., 2012). Genetic manipulation to overexpress GADD34 (also known as PPP1R15A), a stress-induced eIF2α-specific phosphatase, has been shown to terminate UPR signaling and allow translational recovery, thereby rescuing synaptic deficits and neuronal loss and significantly increasing survival (Moreno et al., 2012). Similarly, pharmacological inhibition of PERK activity prevents UPR-mediated synthesis repression and abrogated disease development in mice (Moreno et al., 2013). Therefore, UPR and downstream events play a critical role in prion-induced neurodegeneration, with manipulation of the process to fine-tune protein synthesis possibly representing a therapeutic avenue for prion disease.

The above study raises questions of how extracellular PrP^Sc aggregates induce intracellular ER stress. Other mediators may exist to bridge this gap. Grafting PrP^C-overexpressing neural tissue to Prnp^−/− brain and infecting the graft with prions demonstrated that expression of PrP^C on the cell membrane is required for prion-induced neurotoxicity, as PrP^Sc that accumulated in the graft did not damage the surrounding Prnp^−/− tissues (Brandner et al., 1996). Among the many reported molecules interacting with PrP^C are group-I metabotropic glutamate receptors (mGluRs) (Beraldo et al., 2011; Um et al., 2013). An abnormal mGluR1 (GRM1)-mediated pathway has been observed in CJD and mouse models of BSE (Rodriguez et al., 2005, 2006). Interestingly, pharmacological inhibition or genetic ablation of mGluRs shows neuroprotective effects in both ex vivo and in vivo prion-infection experiments, suggesting that the group-I mGluRs represent a link between PrP^Sc and UPR (Goniotaki et al., 2017) (see poster). Nevertheless, other nonredundant factors may also be involved, as intervention with mGluR function shows only moderate protection (Goniotaki et al., 2017).

Although neurons are the main cells affected by prion, microglial activation and astrogliosis are conspicuous in prion-infected brains (Aguzzi and Zhu, 2017). A recent longitudinal study using RNA sequencing (RNA-seq) of prion-infected mouse brains found that glia-related gene expression changes occur coincidently with the appearance of clinical symptoms, suggesting that functional alterations in glia may be the driver of prion-induced neurodegeneration (Sorce et al., 2020). A cell-type-specific ribosome profiling of prion-infected mouse brain again revealed that extensive molecular changes were detected in glia, while only minor alterations were observed in neurons, implying that the abnormal glial phenotype suffices to cause prion disease (Scheckel et al., 2020).

Microglia are the primary resident macrophages in the brain and can exert both beneficial and detrimental effects. The role of microglia in prion pathogenesis has been assessed by pharmacogenetic ablation of microglia in both organotypic cultured slices and in vivo (Zhu et al., 2016). Here, microglial ablation led to enhanced PrP^Sc deposition and deteriorated prion pathology, suggesting that microglia play an overall neuroprotective role in prion disease by clearing prions (Zhu et al., 2016). Recent single-cell RNA-seq studies have revealed microglial heterogeneity in various mouse models of neurodegenerative diseases (Hammond et al., 2019; Jordao et al., 2019; Keren-Shaul et al., 2017; Li et al., 2019; Marschallinger et al., 2020; Masuda et al., 2019; Mathys et al., 2017). We therefore speculate that, although microglia are generally neuroprotective in prion disease, prion-induced microglial activation is an elaborate and multistep process (see poster). Activated microglia may consist of a mixture of heterogeneous subpopulations with distinct functions. The molecular mediators of the prion phagocytosis and clearance remain to be deciphered. The opsonin milk fat globule epidermal growth factor 8 (MFGE8), but not its homolog developmental endothelial locus-1 (Del-1; also known as EDIL3), contributes to prion clearance under certain conditions (Kranich et al., 2010; Zhu et al., 2019). Although triggering receptor expressed on myeloid cells-2 (TREM2) and macrophage scavenger receptor 1 (Msr1) are involved in phagocytosis of amyloid β (Aβ), the main component of amyloid plaques observed in Alzheimer's disease (Frenkel et al., 2013; Wang et al., 2015) (see also Box 1), they are not major players in prion clearance, suggesting that Aβ and prion adopt distinct mechanisms for their phagocytosis and clearance (Li et al., 2021a; Zhu et al., 2015).

Astrocytes represent the most abundant glial cells in the central nervous system (CNS) and have diverse physiological functions (Santello et al., 2019). In prion disease, astrocytes and neurons are considered primary sites of prion propagation. Previous studies have shown PrP^Sc deposits in astrocytes of both prion-affected patients and rodents (DeArmond et al., 1987; Diedrich et al., 1991; Lasmezas et al., 1996; Liberski, 1987; Na et al., 2007). Expressing PrP^C specifically in astrocytes led Prnp^−/− mice to regain the susceptibility to prion infection and restored PrP^Sc propagation in astrocytes (Raeber et al., 1997), although the specificity of the glial fibrillary acidic protein (GFAP) promoter used remains questionable, as an ectopic activity has been observed in neurons and ependyma (Zhuo et al., 2001). Primary astrocytes and human induced pluripotent stem cell (iPSC)-derived astrocytes, as well as an immortalized mouse astrocyte cell line are able to replicate and propagate prions (Cronier et al., 2004; Krejciova et al., 2017; Tahir et al., 2020), suggesting that astrocytes play an important role in prion pathogenesis. Indeed, a recent study demonstrated that dysregulated astrocytic p-PERK signaling causes astrocytes to have peculiar reactivity states, resulting in a loss of synaptic trophism and neuroprotective functions (Smith et al., 2020). Here, specifically blocking astrocytic p-PERK signaling in prion-infected mice could reverse the aberrant activation state and restore their functions, thereby improving behavioral deficits and increasing survival (Smith et al., 2020). This finding was supported by the observations that astrocytes isolated from prion-infected mouse brain are synaptotoxic to primary cultured neurons (Kushwaha et al., 2021). Thus, reactive astrocytes not only propagate prions, but also exert a harmful effect in prion pathogenesis. Owing to the heterogeneity of reactive astrocytes subtypes (Al-Dalahmah et al., 2020; Habib et al., 2020; John Lin et al., 2017; Wu et al., 2017), further studies, such as single cell RNA-seq or astrocyte-specific modulation of certain pathways, are required to delineate the exact role of each subpopulation in prion pathogenesis.

The crosstalk between microglia and astrocytes adds another layer of complexity to the cellular mechanisms of prion disease (see poster). Activated microglia release cytokines and turn astrocytes into a neurotoxic A1 state, which differs from the neuroprotective A2 state (Liddelow et al., 2017). However, mice with reduced A1-like astrocytes show accelerated prion progression (Hartmann et al., 2019), suggesting that the function of reactive astrocytes in prion-infected mouse brains is more intricate than an oversimplified A1/A2 polarization, with molecular features and functions differing between prion disease and other neurodegenerative disorders.

Various neurodegenerative diseases share a common neuropathological feature – that misfolded protein aggregates are present in the CNS of affected patients (Box 1). Although prion diseases are considered the prototype of transmissible neurodegenerative disorders caused by the self-propagating PrP^Sc, emerging evidence from cell culture and animal model experiments indicates that other disease-associated pathological protein aggregates, such as Aβ, tau and α-synuclein, also show intercellular transmissibility similar to PrP^Sc. These misfolded protein aggregates display prion-like behavior and define an expanding spectrum of prionoid (commonly, if less precisely, also termed ‘prion-like’) conditions (Aguzzi, 2009; Aguzzi and Rajendran, 2009). More importantly, Aβ pathology in Alzheimer's disease patients can spread between individuals through growth hormones (Jaunmuktane et al., 2015; Ritchie et al., 2017) and dura matter transplantation (Frontzek et al., 2016; Hamaguchi et al., 2016; Kovacs et al., 2016), or even contaminated neurosurgical instruments (Jaunmuktane et al., 2018). In the case of α-synuclein, Parkinson's disease patients who underwent transplantation of fetal mesencephalic dopaminergic neurons into the striatum to compensate for the lost neurons developed α-synuclein-positive Lewy bodies in the grafted neurons (Kordower et al., 2008; Li et al., 2008). Similarly, patients with Huntington's disease who received fetal striatal transplants showed mutant huntingtin (mHtt) aggregates in the grafts (Maxan et al., 2018). All these observations highlight the potential transmission of misfolded protein aggregates between individuals.

Notably, iatrogenic transmission of Aβ pathology was only observed in patients who received systemic injections or intracerebral exposure of contaminated materials (Frontzek et al., 2016; Jaunmuktane et al., 2015, 2018). Human brain specimens analyzed in these studies did not present all the features of disease-specific neuropathology. For instance, tauopathy was minimal or absent in most Alzheimer's disease-related samples (Cali et al., 2018; Jaunmuktane et al., 2015). Furthermore, most patients did not develop clinical symptoms, such as progressive cognitive impairment or dementia (Lauwers et al., 2020), which might be due to the relatively slower rate of misfolded protein propagation and disease progression compared to prion diseases. So far, no evidence suggests that Alzheimer's disease and other neurodegenerative diseases except CJD are transmissible between individuals or can lead to an epidemic, rendering them profoundly distinct from prion diseases. Whether these neurodegenerative disorders might be transmissible between humans warrants further investigation. Nevertheless, these observations have raised concerns over public health and laboratory safety. For example, specialized decontamination procedures of surgical instruments should be considered to ensure complete removal of misfolded proteins with prionoid potential.

The mechanisms underlying the neurotoxicity of various misfolded proteins are complex and remain to be fully elucidated. PrP^C is indispensable for prion pathogenesis, since mice lacking PrP^C are resistant to prion infection and neurotoxicity (Brandner et al., 1996; Bueler et al., 1993). Different prion strains, supposedly possessing distinct conformations, elicit neurotoxicity that depends on the presence of PrP^C on the neuronal cell membrane, suggesting that PrP^C may be able to bind other β-sheet-rich proteins and mediate neurodegeneration (Resenberger et al., 2011; Sigurdson et al., 2019). Indeed, PrP^C has been identified as a receptor for Aβ that induces neuronal death as well as memory and behavioral deficits (Lauren et al., 2009). Although controversial results have been reported (Balducci et al., 2010; Calella et al., 2010; Cisse et al., 2011; Kessels et al., 2010), it is widely accepted that PrP^C interacts with Aβ oligomers, and mGluR5 (also known as GRM5) and the kinase Fyn may be involved in initiating the neurotoxic signaling cascade (Larson et al., 2012; Um et al., 2013). PrP^C might be also involved in Aβ oligomer-induced tau hyperphosphorylation, thus providing a link between these two pathological hallmarks of Alzheimer's disease (Gomes et al., 2019) (see also Box 1). Similarly, PrP^C may act as a cellular receptor for α-synuclein aggregates, facilitating their cellular uptake and spread within the brain, and inducing synaptic impairment through a pathway that also involves mGluR5 and Fyn (Ferreira et al., 2017) (see poster).

A more recent study found that PrP^C might be a more-generalized receptor for protein oligomers containing β-sheet-rich structures, including tau and α-synuclein, and mediates neurotoxicity (Corbett et al., 2020). Accordingly, PrP^C may play a central role in a broad spectrum of neurodegenerative diseases that are caused by Aβ, tau and α-synuclein (Corbett et al., 2020). Considering that mGluR5 forms a complex with PrP^C to mediate neurotoxicity of Aβ and α-synuclein, further studies are required to explore whether this pathway is shared by other prionoids or whether any other signaling cascades are involved.

Diagnostic conformation of prion disease is currently only possible through post-mortem examination. The clinical presentation and ancillary methods mainly based on electroencephalogram (EEG) and MRI imaging combined with biochemical detection of 14-3-3 protein (a specific neuronal biomarker for premortem diagnosis of human prion diseases) in cerebrospinal fluid (CSF) provide clues for a preliminary diagnosis (Zerr et al., 2009). However, these traditional methods suffer from limitations of sensitivity and specificity. In recent years, efforts have been made to develop new diagnostic tools for the diagnosis of prion disease. Real-time quaking-induced conversion (RT-QuIC) represents a major improvement in the clinical diagnosis of prion diseases. RT-QuIC is an in vitro conversion assay that uses recombinant prion proteins as substrates to measure the seeding activity of the sample by shaking and incubation cycles, followed by the detection of aggregates by thioflavin-T (ThT) (Atarashi et al., 2011; Wilham et al., 2010). It is important to acknowledge that the principle of RT-QuIC is mostly based on the hypothesis of its inventor, Claudio Soto, that cycles of fibril breakage and fibril elongation [protein misfolding cyclical amplification (PMCA)] may be suitable for prion amplification (Saborio et al., 2001). However, compared to PMCA, RT-QuIC mostly replaces a sonication step with swirling, and replaces brain homogenates with recombinant PrP^C as substrates, which simplifies the procedure (Atarashi et al., 2011; Wilham et al., 2010). Indeed, the RT-QuIC assay has already been included in the diagnostic criteria for sporadic CJD, the most-prevalent human prion disease (Hermann et al., 2021). Nonetheless, it is still challenging to discriminate different subtypes of sCJD by RT-QuIC. Importantly, owing to its high sensitivity, RT-QuIC has been further developed to detect the seeding activity of other disease-associated protein aggregates and for diagnosis of other neurodegenerative diseases (Fairfoul et al., 2016; Kraus et al., 2019; Rossi et al., 2020; Saijo et al., 2017).

Prion disease are so far incurable, despite considerable efforts to cure or ameliorate the disease. Therapeutic strategies include lowering PrP^C expression, abrogating conversion of PrP^C into PrP^Sc and targeting the downstream neurotoxic signaling cascade (Aguzzi et al., 2018, 2013) (see poster). Various compounds, including flupirtine (Perovic et al., 1998), quinacrine (Korth et al., 2001), doxycycline (Tremblay et al., 1998), pentosan polysulfate (Farquhar et al., 1999) and others, have been shown to block PrP^C-to-PrP^Sc conversion in cell culture or to prolong the survival of prion-infected mice. Eventually, however, all of them have displayed only minimal or no beneficial effects against human prions (Aguzzi et al., 2018; Collinge et al., 2009; Haik et al., 2014; Newman et al., 2014; Otto et al., 2004). These disappointing results have prompted research to explore new therapeutical avenues, such as rationally designed chemical compounds, immunotherapies or gene therapies. Luminescent conjugated polymers have been shown to be able to bind amyloid fibrils and stabilize PrP^Sc aggregates, thereby decreasing the infectivity and prolonging the survival of prion-infected mice (Herrmann et al., 2015). Both active and passive immunization have been investigated in animal models of prion disease and show promise in delaying prion progression (Heppner et al., 2001; Peretz et al., 2001; Sigurdsson et al., 2002; Souan et al., 2001). However, some antibodies against certain epitopes of prion protein show neurotoxicity (Sonati et al., 2013); therefore, any attempt at immunotherapy or immunoprophylaxis of prion disease should avoid these potential untoward effects. Notably, a controversial approval of Aducanumab, a human monoclonal antibody against Aβ oligomers and fibrils, for the treatment of Alzheimer's disease in human has elicited debates on the effectiveness of immunotherapy for neurodegenerative diseases (https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease). Aducanumab lowers Aβ loads in the brain, but it is unclear whether it improves cognitive outcome in most patients (Alexander et al., 2021; Sevigny et al., 2016; Walsh et al., 2021). The reasons for the failures in the development of effective immunotherapies for neurodegenerative diseases include the bioavailability of the antibodies to the CNS, their limited efficacy in late disease stages and the vast heterogeneity of disease pathogenesis.

Recently, it has been shown that PrP^C-lowering anti-sense oligonucleotides (ASOs) given prophylactically or post-infection are able to significantly extend the survival of prion-infected mice, independent of prion strains or disease stages (Minikel et al., 2020; Raymond et al., 2019), supporting the notion that PrP^C-lowering therapeutics may be a promising strategy to combat prion disease.

Newly developed technologies are enabling high-resolution structural models of PrP^Sc. Using the new Prnp^−/− mouse model, novel physiological functions of PrP^C have been uncovered or validated. In parallel, the cellular and molecular mechanisms of prion-induced neurodegeneration have also been revealed. Notably, the prion concept has been expanded based on recent findings of prionoid or prion-like phenomena for several disease-associated proteins. Additionally, the involvement of PrP^C in other neurodegenerative diseases suggests a delicate crosstalk between prion and prionoids. Therefore, although prion diseases are considered unique compared to other neurodegenerative disorders, mounting evidence indicates that they may share the same or similar underlying mechanisms, including misfolded protein propagation and neurotoxicity. The prion and prionoid concepts suggest that further studies on prion disease hold promise to deepen our understanding on the pathogenesis of a panoply of neurodegenerative conditions.

The authors thank Elisabeth J. Rushing for reading and editing the article.

Individual poster panels are available for downloading at https://journals.biologists.com/jcs/article-lookup/doi/10.1242/jcs.245605#supplementary-data