RARE DISEASE
Variant Creutzfeldt-Jakob disease
Variant Creutzfeldt-Jakob disease
Variant Creutzfeldt-Jakob disease
Synonyms: Variant MCJ, vCJD
Synonyms: Variant MCJ, vCJD
Synonyms: Variant MCJ, vCJD
Drug discovery
0
drugs
With orphan designations
Overview
Variant Creutzfeldt-Jakob Disease (vCJD) is a fatal prion disorder linked to consumption of bovine spongiform encephalopathy (BSE)-contaminated beef. It manifests with early psychiatric symptoms (e.g., depression, anxiety) followed by rapid neurological decline (ataxia, dementia, myoclonus). Diagnosis requires brain biopsy or post-mortem analysis. Median survival is 13–14 months, with no curative therapies available [1][8][15].
Population
Rare: ~230 global cases since 1996, primarily in the UK [9][16].
Affects younger adults (median age: 28 years); all confirmed cases involve methionine homozygosity at codon 129 of the PRNP gene [8][15].
Risk factors include exposure to BSE-tainted products or contaminated blood transfusions [2][11].
Categories: rare neurological diseases
Research Papers
557 drug discovery papers about Variant Creutzfeldt-Jakob disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
557 drug discovery papers about Variant Creutzfeldt-Jakob disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-10 | Formic acid treatment drastically reduces sporadic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease infectivity in histological samples as tested in a high-sensitivity mouse bioassay.
Formic acid treatment is widely used in diagnostic neuropathology to reduce the infectivity of prion-containing tissues; however, quantitative in vivo evidence supporting its effectiveness under routine laboratory conditions remains limited. Here, we assessed the impact of formalin fixation and formic acid treatment on the infectivity of type 1 sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD) prions using highly sensitive transgenic mouse models overexpressing human-PrP M129 (Hu-Tg340) or bovine PrP (Bo-Tg110). Brain tissues were processed under conditions closely resembling standard histopathological workflows and tested as untreated, formalin-fixed or formalin-plus-formic-acid-treated inocula. Untreated samples produced short incubation times and full attack rates, whereas formalin fixation caused only a modest prolongation of incubation times. In contrast, formic acid treatment markedly extended incubation times and reduced attack rates for sCJD. Based on incubation-time interpolation, the estimated infectivity reductions were on the order of 4.4 log₁₀ for vCJD and 5 log₁₀ for sCJD. These estimates indicate a major reduction in infectious titre under the conditions tested, although residual infectivity was still detected. The findings support formic acid treatment as an important risk-reduction step in routine neuropathology workflows for the two prion strains examined.
2026-05-08 | Conjecture for a free radical epimerization process in Alzheimer, Parkinson, Lewy body, amyotrophic lateral sclerosis, progressive Supranuclear Palsy and Creutzfeldt Jakob diseases.
Brain protease-resistant misfolded proteins have been described in Alzheimer (AD), Parkinson (PD), Lewy Body (LBD), Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy (PSP) and Creutzfeldt Jakob (CJD) diseases. The role of free radicals in generating these protease resistant structures has been experimentally demonstrated in prion bovine spongiform encephalopathy (BSE), when manganese is substituted for copper (Cu), in bovine brain homogenates in reductive medium, while Cu protective effect against free radicals can be restored by Cu supplementation in oxidative medium. These facts can suggest a free radical-induced epimerization process in neuroprotein misfolding leading to the transformation of physiological L-amino acid brain proteins into abnormal D-structures which will be deposited in the brain as observed in neurodegenerative diseased brains. A blood Cu increase, not ceruloplasmin (CP) bound correlated with a Cu increase in the cerebrospinal fluid (CSF) and a Cu decrease in the brain have been described in AD, PD, ALS, or CJD. This indicates that following neuronal death, Cu might be expelled from brain proteins and subsequent to redistribution between brain, CSF and blood, it will result a brain Cu deficiency and a decrease in Cu brain protection against free radicals. In the aim of repairing this deficiency and slow down the neurodegenerative disease process, a brain Cu complexes vectorization through the blood-brain barrier might restore brain Cu homeostasis.
2025-08-06 | Molecular Insights into Prion Degradation in Creutzfeldt Jakob Disease’s Challenges and Future Directions: A Review
Creutzfeldt-Jakob Disease (CJD) is a rare, fatal neurodegenerative disorder characterized by the accumulation of misfolded prion proteins (PrP^Sc) in the central nervous system. This review explores the molecular dynamics of prion misfolding and its implications for disease progression, with a particular focus on cellular degradation pathways. Key proteolytic systems, including the ubiquitin-proteasome system and the autophagy-lysosome pathway, are critically analyzed for their roles in the clearance of PrP^Sc. Special emphasis is placed on lysosomal involvement, where autophagosomes fuse to form autolysosomes, facilitating the breakdown of pathogenic proteins. The interplay between proteases and molecular chaperones in maintaining protein homeostasis is also discussed. Neuropathologically, CJD is marked by spongiform alterations, neuronal loss, and gliosis. Clinically, the disease presents with rapidly progressive dementia, motor impairments, and psychiatric symptoms. The heterogeneity of CJD is addressed by outlining its sporadic, familial, iatrogenic, and variant subtypes. Recent advances in diagnostic techniques, including real-time quaking-induced conversion (RT-QuIC) in peripheral tissues, as well as the integration of machine learning tools and AI-assisted biomarker discovery, are highlighted. Emerging therapeutic strategies targeting proteolytic and lysosomal pathways are also reviewed, offering potential for future intervention in this currently untreatable disease.
2025-06-26 | Prion-induced ferroptosis is facilitated by RAC3.
Prions are infectious agents that initiate transmissible spongiform encephalopathies, causing devastating neuronal destruction in Creutzfeldt-Jakob and Kuru disease. Rapid cell death depends on presence of the endogenous prion protein PrPC, but its mechanistic contribution to pathogenesis is unclear. Here we investigate the molecular role of PrPC, reactive oxygen species and lipid metabolism in ferroptosis susceptibility, a regulated cell death process characterized by lipid peroxidation. We discover that elevated expression of the cellular prion PrPC creates a relaxed oxidative milieu that favors accumulation of unsaturated long-chain phospholipids responsible for ferroptotic death. This condition is sustained by the luminal protein glutathione peroxidase 8, which detoxifies reactive species produced by protein misfolding. Consequently, both PrPC and infectious Creutzfeldt-Jakob disease (CJD) prions trigger ferroptotic markers and sensitization. This lethality is further enhanced by RAC3, a small GTPase. Depletion of RAC3 is observed solely in pathologically afflicted cortices in CJD patients, revealing a synergistic modulation of lipids and reactive species that drives ferroptosis susceptibility. Together, the results show that PrPC initially suppresses oxidative stress, attenuates cellular defenses, and establishes a systemic vulnerability to the ferroptotic cascade. These results provide insight into the mechanism underlying regulation of ferroptosis in prion diseases and highlight potential therapeutic targets for diseases involving dysregulated cell death processes.
2025-06-20 | Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism.
Prion diseases are fatal, infectious, and incurable neurodegenerative conditions affecting humans and animals, caused by the misfolding of the cellular prion protein (PrPC) into its pathogenic isoform, PrPSc. In humans, sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent prion disease. Recently, we demonstrated that treatment with the FDA-approved anti-HIV drug efavirenz (EFV) significantly reduced PrPSc and extended survival of scrapie prion-infected mice. Among other effects, EFV activates the brain-specific cholesterol-metabolizing enzyme, CYP46A1, which converts cholesterol into 24S-hydroxycholesterol (24S-HC). However, drugs effective against scrapie prions often fail in human prion diseases, and a relation of the antiprion effects of EFV to CYP46A1 activation is not established. Thus, we evaluated EFV treatment in mice overexpressing human PrPC infected with human sCJD prions. Oral, low-dose EFV treatment starting at 30 or 130 days postinfection significantly slowed disease progression and extended their survival. At early clinical stage, we observed reduced PrPSc accumulation, decreased cholesterol and lipid droplet content, and elevated CYP46A1 and 24S-HC levels in EFV-treated mice. Overexpression of CYP46A1 in prion-infected neuronal cells reduced PrPSc levels and increased 24S-HC, indicating that antiprion effects of EFV correlate with CYP46A1 activation. These findings highlight EFV as a safe and efficacious therapeutic candidate for human prion diseases.
vaccines
2023-02-11 | Vaccines for prion diseases: a realistic goal?
Abstract Prion diseases are fatal infectious neurodegenerative disorders and prototypic conformational diseases, caused by the conformational conversion of the normal cellular prion protein (PrP C ) into the pathological PrP Sc isoform. Examples are scrapie in sheep and goat, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids, and Creutzfeldt–Jacob disease (CJD) in humans. There are no therapies available, and animal prion diseases like BSE and CWD can negatively affect the economy, ecology, animal health, and possibly human health. BSE is a confirmed threat to human health, and mounting evidence supports the zoonotic potential of CWD. CWD is continuously expanding in North America in numbers and distribution and was recently identified in Scandinavian countries. CWD is the only prion disease occurring both in wild and farmed animals, which, together with extensive shedding of infectivity into the environment, impedes containment strategies. There is currently a strong push to develop vaccines against CWD, including ones that can be used in wildlife. The immune system does not develop a bona fide immune response against prion infection, as PrP C and PrP Sc share an identical protein primary structure, and prions seem not to represent a trigger for immune responses. This asks for alternative vaccine strategies, which focus on PrP C -directed self-antibodies or exposure of disease-specific structures and epitopes. Several groups have established a proof-of-concept that such vaccine candidates can induce some levels of protective immunity in cervid and rodent models without inducing unwanted side effects. This review will highlight the most recent developments and discuss progress and challenges remaining.
2019-02-01 | Clinical trials of prion disease therapeutics
Prion-related encephalopathies or transmissible spongiform encephalopathies (TSEs) are a group of rare progressive neurodegenerative disorders that are invariably fatal with often only six months elapsing from diagnosis to patient death. This makes the development of effective therapeutic strategies challenging. Nonetheless, compounds have been identified in animal models of TSE that prolong survival and, in some instances, eradicate the disease. These have been tested in the clinic, although with modest or negative outcomes. While little progress has been made over the last decade, new findings that include the ability to identify prion aggregates at low levels in biological fluids and cells may lead to the development of early-stage biomarkers for TSE. An increased focus on immunotherapeutic approaches to TSE may result in the development of novel preventive approaches for TSE.
2016-04-14 | Methods and Protocols for Developing Prion Vaccines
Prion diseases denote a distinct form of infectivity that is based in the misfolding of a self-protein (PrPC) into a pathological, infectious conformation (PrPSc). Efforts to develop vaccines for prion diseases have been complicated by the potential dangers that are associated with induction of immune responses against a self-protein. As a consequence, there is considerable appeal for vaccines that specifically target the misfolded prion conformation. Such conformation-specific immunotherapy is made possible through the identification of vaccine targets (epitopes) that are exclusively presented as a consequence of misfolding. An immune response directed against these targets, termed disease-specific epitopes (DSEs), has the potential to spare the function of the native form of the protein while clearing, or neutralizing, the infectious isomer. Although identification of DSEs represents a critical first step in the induction of conformation-specific immune responses, substantial efforts are required to translate these targets into functional vaccines. Due to the poor immunogenicity that is inherent to self-proteins, and that is often associated with short peptides, substantial efforts are required to overcome tolerance-to-self and maximize the resultant immune response following DSE-based immunization. This often includes optimization of target sequences in terms of immunogenicity and development of effective formulation and delivery strategies for the associated peptides. Further, these vaccines must satisfy additional criteria from perspectives of specificity (PrPC vs. PrPSc) and safety (antibody-induced template-driven misfolding of PrPC). The emphasis of this report is on the steps required to translate DSEs into prion vaccines and subsequent evaluation of the resulting immune responses.
2014-09-30 | Prospects for safe and effective vaccines against prion diseases
Prion diseases are subacute neurodegenerative diseases that affect humans and animals. An abnormally folded isoform (PrPSc) of the host cellular prion protein is considered to constitute the major, if not sole, component of the infectious prion. The occurrence of variant Creutzfeldt–Jakob disease in humans most likely arose due to consumption of food contaminated with bovine spongiform encephalopathy prions. The demonstration that some prion infections may have the capacity to transmit to other species, especially humans, has focused attention on the development of safe and effective vaccines against these invariably fatal and currently incurable diseases. Although much effort has been invested in the development of safe and effective anti-PrP vaccines, many important issues remain to be resolved.
2013-10-20 | Evidence for Prion-Like Mechanisms in Several Neurodegenerative Diseases: Potential Implications for Immunotherapy
Transmissible spongiform encephalopathies (TSEs) are fatal, untreatable neurodegenerative diseases. While the impact of TSEs on human health is relatively minor, these diseases are having a major influence on how we view, and potentially treat, other more common neurodegenerative disorders. Until recently, TSEs encapsulated a distinct category of neurodegenerative disorder, exclusive in their defining characteristic of infectivity. It now appears that similar mechanisms of self-propagation may underlie other proteinopathies such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Huntington’s disease. This link is of scientific interest and potential therapeutic importance as this route of self-propagation offers conceptual support and guidance for vaccine development efforts. Specifically, the existence of a pathological, self-promoting isoform offers a rational vaccine target. Here, we review the evidence of prion-like mechanisms within a number of common neurodegenerative disorders and speculate on potential implications and opportunities for vaccine development.
antibodies
2026-06-30 | A scalable, dividing cell model for the robust propagation and quantification of human sporadic Creutzfeldt-Jakob disease prions.
Prion diseases represent a unique biological paradigm with mechanistic parallels to other neurodegenerative conditions like Alzheimer's and Parkinson's diseases. However, the study of human prion pathobiology and the development of effective therapeutics has been severely constrained by the inability to propagate human prions in dividing cells-forcing reliance on costly and slow animal bioassays. Here, we report the generation of EKV cells-a humanized cell model which supports the robust, indefinite propagation of sporadic Creutzfeldt-Jakob disease (sCJD) prions. We demonstrate that these cells replicate bona fide human prion infectivity in culture-cell lysates induce lethal neurodegeneration in humanized mice that is clinically and neuropathologically indistinguishable from inoculation with sCJD-infected brain tissue. We use EKV cells to develop the Human Prion Assay (HPA), which quantifies sCJD infectivity with sensitivity comparable to gold-standard mouse bioassay, while reducing the experimental timeline from years to weeks. Furthermore, we demonstrate that established sCJD infection can be cured by an anti-prion protein antibody, validating the system as a high-throughput platform for drug discovery. This model bridges a critical translational gap, offering a renewable alternative to animal bioassays, a paradigm to dissect the biology of human sCJD prion disease and screen for therapeutic agents.
2026-02-27 | Human Prion Disease: Pathogenesis, Diagnosis and Public Health.
Background: Prion diseases represent a group of rare, progressive, and invariably fatal neurodegenerative disorders. Their hallmark is the infectious nature of the misfolded prion protein (PrP^Sc), which propagates by inducing conformational changes in the physiological form (PrP^C). Despite advances in basic science, these disorders still pose major clinical and therapeutic challenges. Methods: A narrative review of the scientific literature was conducted across major biomedical databases, including PubMed, Scopus, Web of Science, and Google Scholar, covering publications up to January 2025. In addition, we describe an illustrative clinical case of a young patient with probable iatrogenic Creutzfeldt-Jakob disease following corneal transplantation, used to highlight diagnostic uncertainty and infection-control implications. Findings: Evidence confirms that PrP^Sc drives neurodegenerative processes and transmissibility, with phenotypic and genetic variants influencing clinical course and prognosis. From a diagnostic perspective, neuroimaging techniques and cerebrospinal fluid biomarkers have undergone substantial refinement, with RT-QuIC emerging as a highly specific and sensitive assay. Therapeutic options remain unsatisfactory: no treatment has shown a significant impact on survival. However, innovative strategies (including monoclonal antibodies, gene-based interventions, and modulation of PrP^C) represent promising avenues of investigation. Conclusions: Prion diseases remain an unresolved challenge at the intersection of neurology and infectious diseases. Earlier diagnosis through advanced biomarkers and continued development of targeted therapies are essential to improve patient management, while the persistence of iatrogenic cases underscores the ongoing relevance of surveillance and preventive strategies in clinical practice.
2022-04-25 | Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt-Jakob disease: evaluation of a first-in-human treatment programme.
Human prion diseases, including Creutzfeldt-Jakob disease (CJD), are rapidly progressive, invariably fatal neurodegenerative conditions with no effective therapies. Their pathogenesis involves the obligate recruitment of cellular prion protein (PrPC) into self-propagating multimeric assemblies or prions. Preclinical studies have firmly validated the targeting of PrPC as a therapeutic strategy. We aimed to evaluate a first-in-human treatment programme using an anti-PrPC monoclonal antibody under a Specials Licence. We generated a fully humanised anti-PrPC monoclonal antibody (an IgG4κ isotype; PRN100) for human use. We offered treatment with PRN100 to six patients with a clinical diagnosis of probable CJD who were not in the terminal disease stages at the point of first assessment and who were able to readily travel to the University College London Hospital (UCLH) Clinical Research Facility, London, UK, for treatment. After titration (1 mg/kg and 10 mg/kg at 48-h intervals), patients were treated with 80-120 mg/kg of intravenous PRN100 every 2 weeks until death or withdrawal from the programme, or until the supply of PRN100 was exhausted, and closely monitored for evidence of adverse effects. Disease progression was assessed by use of the Medical Research Council (MRC) Prion Disease Rating Scale, Motor Scale, and Cognitive Scale, and compared with that of untreated natural history controls (matched for disease severity, subtype, and PRNP codon 129 genotype) recruited between Oct 1, 2008, and July 31, 2018, from the National Prion Monitoring Cohort study. Autopsies were done in two patients and findings were compared with those from untreated natural history controls. We treated six patients (two men; four women) with CJD for 7-260 days at UCLH between Oct 9, 2018, and July 31, 2019. Repeated intravenous dosing of PRN100 was well tolerated and reached the target CSF drug concentration (50 nM) in four patients after 22-70 days; no clinically significant adverse reactions were seen. All patients showed progressive neurological decline on serial assessments with the MRC Scales. Neuropathological examination was done in two patients (patients 2 and 3) and showed no evidence of cytotoxicity. Patient 2, who was treated for 140 days, had the longest clinical duration we have yet documented for iatrogenic CJD and showed patterns of disease-associated PrP that differed from untreated patients with CJD, consistent with drug effects. Patient 3, who had sporadic CJD and only received one therapeutic dose of 80 mg/kg, had weak PrP synaptic labelling in the periventricular regions, which was not a feature of untreated patients with sporadic CJD. Brain tissue-bound drug concentrations across multiple regions in patient 2 ranged from 9·9 μg per g of tissue (SD 0·3) in the thalamus to 27·4 μg per g of tissue (1·5) in the basal ganglia (equivalent to 66-182 nM). Our academic-led programme delivered what is, to our knowledge, the first rationally designed experimental treatment for human prion disease to a small number of patients with CJD. The treatment appeared to be safe and reached encouraging CSF and brain tissue concentrations. These findings justify the need for formal efficacy trials in patients with CJD at the earliest possible clinical stages and as prophylaxis in those at risk of prion disease due to PRNP mutations or prion exposure. The Cure CJD Campaign, the National Institute for Health Research UCLH Biomedical Research Centre, the Jon Moulton Charitable Trust, and the UK MRC.
2021-08-18 | Exploring Drug and Antibody-Based Treatment Options for Creutzfeldt-Jakob Disease
Creutzfeldt-Jakob Disease (CJD) is a neurodegenerative disease characterized by mutant PrP prion proteins, which accumulates and impairs the function of wild-type PrPc proteins. The interaction of prion proteins with wild-type proteins converts the PrPc proteins to mutant PrP proteins. These mutant prion proteins lead to neural tissue degradation and other nervous system problems that can eventually lead to death. The use of antibodies to target and destroy prion proteins can be used to decrease PrP levels that can stop CJD progression. The binding affinities of different anti-PrP Fab antibodies are analyzed to determine which antibody best binds to PrP proteins and targets them for destruction. Through antibody-based targeting of prion proteins, potential treatment methods could be developed for CJD. In addition, the use of drugs, such as quinacrine and doxycycline, also show short-term effects in decreasing the progression of CJD. These drugs extend the average lifespan of tested subjects with CJD but also lead to the development of drug-resistant prion proteins that eventually cause the death of the subject affected by CJD.
2020-04-21 | Complement 3+-astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia.
Astrogliosis and activation of microglia are hallmarks of prion diseases in humans and animals. Both were viewed to be rather independent events in disease pathophysiology, with proinflammatory microglia considered to be the potential neurotoxic species at late disease stages. Recent investigations have provided substantial evidence that a proinflammatory microglial cytokine cocktail containing TNF-α, IL-1α and C1qa reprograms a subset of astrocytes to change their expression profile and phenotype, thus becoming neurotoxic (designated as A1-astrocytes). Knockout or antibody blockage of the three cytokines abolish formation of A1-astrocytes, therefore, this pathway is of high therapeutic interest in neurodegenerative diseases. Since astrocyte polarization profiles have never been investigated in prion diseases, we performed several analyses and could show that C3+-PrPSc-reactive-astrocytes, which may represent a subtype of A1-astrocytes, are highly abundant in prion disease mouse models and human prion diseases. To investigate their impact on prion disease pathophysiology and to evaluate their potential therapeutic targeting, we infected TNF-α, IL-1α, and C1qa Triple-KO mice (TKO-mice), which do not transit astrocytes into A1, with prions. Although formation of C3+-astrocytes was significantly reduced in prion infected Triple-KO-mice, this did not affect the amount of PrPSc deposition or titers of infectious prions. Detailed characterization of the astrocyte activation signature in thalamus tissue showed that astrocytes in prion diseases are highly activated, showing a mixed phenotype that is distinct from other neurodegenerative diseases and were therefore termed C3+-PrPSc-reactive-astrocytes. Unexpectedly, Triple-KO led to a significant acceleration of prion disease course. While pan-astrocyte and -microglia marker upregulation was unchanged compared to WT-brains, microglial homeostatic markers were lost early in disease in TKO-mice, pointing towards important functions of different glia cell types in prion diseases.
proteins
2025-04-30 | Abnormal Expression of Proteolytic Stress-Related Proteins and Protective Effect of Fibrinolytic Enzymes in Prion Diseases.
Prion diseases are fatal, irreversible, and infectious neurodegenerative diseases caused by proteinase K-resistant prion protein (PrPSc). Against PrPSc, several endogenous proteases involved in cellular degradation mechanisms can be activated to remove PrPSc. However, since PrPSc shows proteinase K resistance, we presumed that undegradable PrPSc induces positive feedback on the overactivation of the cellular degradation mechanisms and is correlated with proteolytic stress and exacerbation of the progression of prion diseases. We investigated the expression pattern of proteolytic stress-related proteins in the brains of ME7 scrapie-infected mice at 7 months postinfection and sporadic Creutzfeldt-Jakob disease (CJD) patients using western blotting and immunohistochemistry (IHC). In addition, we analyzed the 3D structure and binding complexes of prion protein (PrP) with nattokinase and lumbrokinase using in silico programs, including SWISS-MODEL and HawkDock. To fundamentally reduce proteolytic stress by the degradation of PrPSc, we performed an in vitro evaluation of the PrPSc degradation abilities of fibrinolytic enzymes, including nattokinase and lumbrokinase. Furthermore, we assessed the protective effects of nattokinase and lumbrokinase in ME7 scrapie-infected mice. We observed an abnormal accumulation of proteolytic stress-related proteins, including CD10, cathepsin B, cathepsin D, and matrix metalloproteinase 9 (MMP9), in the brains of ME7 scrapie-infected mice and sporadic CJD patients. In addition, we identified that nattokinase and lumbrokinase can stably bind to PrP. Furthermore, we identified significant in vitro degradation of PrPSc derived from ME7 scrapie-infected mice and sporadic CJD patients by nattokinase and lumbrokinase. Last, we found in vivo protective effects of nattokinase and lumbrokinase against prion disease in ME7 scrapie-infected mice. To the best of our knowledge, this is the first report on the identification of proteolytic stress-related novel potential biomarkers and the therapeutic potential of nattokinase and lumbrokinase for prion diseases.
2023-08-31 | Fibronectin: a natural barrier against prion infection
Abstract A distinctive signature of the prion diseases is the accumulation of the pathogenic isoform of the prion protein, PrP Sc , in the central nervous system of prion-affected humans and animals. PrP Sc is also found in peripheral tissues, raising concerns about the potential transmission of pathogenic prions through human food supplies and posing a significant risk to public health. Although muscle tissues are considered to contain levels of low prion infectivity, it has been shown that myotubes in culture efficiently propagate PrP Sc . Given the high consumption of muscle tissue, it is important to understand what factors could influence the establishment of a prion infection in muscle tissue. Here we used in vitro myotube cultures, differentiated from the C2C12 myoblast cell line (dC2C12), to identify factors affecting prion replication. A range of experimental conditions revealed that PrP Sc is tightly associated with proteins found in the systemic extracellular matrix (ECM), mostly fibronectin (FN). The interaction of PrP Sc with FN decreased prion infectivity, as determined by standard scrapie cell assay. Interestingly, the prion-resistant reserve cells in dC2C12 cultures displayed a FN-rich ECM while the prion-susceptible myotubes expressed FN at a low level. In agreement with the in vitro results, immunohistopathological analyses of tissues from sheep infected with natural scrapie demonstrated a prion susceptibility phenotype linked to an extracellular matrix with undetectable levels of FN. Conversely, PrP Sc deposits were not observed in tissues expressing FN. These data indicate that extracellular FN may act as a natural barrier against prion replication and that the extracellular matrix composition may be a crucial feature determining prion tropism in different tissues. Author summary Prion diseases are complex fatal neurodegenerative disorders caused by a misfolded form of the cellular protein PrP C (PrP Sc ). Due to the potential zoonotic transmission of these disorders through animal-based food intake, it is crucial to identify the tissues in which PrP Sc can accumulate and what might influence its tropism. Animal muscle (or meat) and related food products are highly consumed, raising concern of the involvement of muscle cells in prion replication. Muscle tissue from prion-affected animals contains low levels of infectivity and PrP Sc is mostly associated with nerve structures rather than myofibers, whereas C2C12 myotubes, a muscle-derived cell type, efficiently replicate prions in vitro and generate high levels of infectivity compared with other cell cultures. We demonstrate a fibronectin-mediated interference with prion infection in differentiated C2C12 cultures that correlates with the findings in tissues from naturally scrapie-infected animals. Our results suggest that extracellular matrix composition, specifically regarding the presence of fibronectin, might determine prion tropism and dissemination.
2023-07-14 | Different tau fibril types reduce prion level in chronically and de novo infected cells
Neurodegenerative diseases are often characterized by the codeposition of different amyloidogenic proteins, normally defining distinct proteinopathies. An example is represented by prion diseases, where the classical deposition of the aberrant conformational isoform of the prion protein (PrPSc) can be associated with tau insoluble species, which are usually involved in another class of diseases called tauopathies. How this copresence of amyloidogenic proteins can influence the progression of prion diseases is still a matter of debate. Recently, the cellular form of the prion protein, PrPC, has been investigated as a possible receptor of amyloidogenic proteins, since its binding activity with Aβ, tau, and α-synuclein has been reported, and it has been linked to several neurotoxic behaviors exerted by these proteins. We have previously shown that the treatment of chronically prion-infected cells with tau K18 fibrils reduced PrPSc levels. In this work, we further explored this mechanism by using another tau construct that includes the sequence that forms the core of Alzheimer's disease tau filaments in vivo to obtain a distinct fibril type. Despite a difference of six amino acids, these two constructs form fibrils characterized by distinct biochemical and biological features. However, their effects on PrPSc reduction were comparable and probably based on the binding to PrPC at the plasma membrane, inhibiting the pathological conversion event. Our results suggest PrPC as receptor for different types of tau fibrils and point out a role of tau amyloid fibrils in preventing the pathological PrPC to PrPSc conformational change.
2022-07-25 | Recombinant ovine prion protein can be mutated at position 136 to improve its efficacy as an inhibitor of prion propagation
Abstract Prion diseases are progressive neurodegenerative disorders with no effective therapeutics. A central event leading to the pathology in the diseases is the conversion of PrP C into PrP Sc and its accumulation in the central nervous system. Previous studies demonstrated that PrP C , recombinant PrP (rPrP) and PrP peptides can inhibit the formation of PrP Sc . Here, the effectiveness of ovine rPrP mutants at codon 136 and peptides derived from this region were assessed for their ability to inhibit PrP Sc replication, using protein misfolding cyclic amplification (PMCA). Based on a rPrP VRQ (rVRQ) genotype background (positions 136, 154 and 171) and mutations at position 136, the most effective inhibitors were V136R, V136K and V136P mutants, with IC50 values of 2–11 nM; activities up to 57 times more potent than rVRQ. rRRQ was also shown to inhibit a range of ruminant prion amplification reactions including with distinct prion strain seeds and substrate PRNP genotypes. The rRRQ was also shown to effectively protect Rov9 cells from scrapie infection when applied at 250 nM. The study demonstrates for the first time that the rPrP sequence can be mutated at sites known to be involved in prion disease susceptibility, to produce inhibitors with improved efficacy.
2022-04-13 | Serpin Signatures in Prion and Alzheimer’s Diseases
Serpins represent the most broadly distributed superfamily of proteases inhibitors. They contribute to a variety of physiological functions and any alteration of the serpin-protease equilibrium can lead to severe consequences. SERPINA3 dysregulation has been associated with Alzheimer's disease (AD) and prion diseases. In this study, we investigated the differential expression of serpin superfamily members in neurodegenerative diseases. SERPIN expression was analyzed in human frontal cortex samples from cases of sporadic Creutzfeldt-Jakob disease (sCJD), patients at early stages of AD-related pathology, and age-matched controls not affected by neurodegenerative disorders. In addition, we studied whether Serpin expression was dysregulated in two animal models of prion disease and AD.Our analysis revealed that, besides the already observed upregulation of SERPINA3 in patients with prion disease and AD, SERPINB1, SERPINB6, SERPING1, SERPINH1, and SERPINI1 were dysregulated in sCJD individuals compared to controls, while only SERPINB1 was upregulated in AD patients. Furthermore, we analyzed whether other serpin members were differentially expressed in prion-infected mice compared to controls and, together with SerpinA3n, SerpinF2 increased levels were observed. Interestingly, SerpinA3n transcript and protein were upregulated in a mouse model of AD. The SERPINA3/SerpinA3nincreased anti-protease activity found in post-mortem brain tissue of AD and prion disease samples suggest its involvement in the neurodegenerative processes. A SERPINA3/SerpinA3n role in neurodegenerative disease-related protein aggregation was further corroborated by in vitro SerpinA3n-dependent prion accumulation changes. Our results indicate SERPINA3/SerpinA3n is a potential therapeutic target for the treatment of prion and prion-like neurodegenerative diseases.
other
2024-06-08 | CLINICALLY PROBABLE SPORADIC CREUTZFELDT JAKOB DISEASE (CJD)
Creutzfeldt-Jakob Disease (CJD) stands at the forefront of neurodegenerative disorders, characterized by rapid progression and devastating neurological deterioration. This review encapsulates the current understanding of CJD, encompassing its epidemiology, etiology, pathogenesis, clinical manifestations, and diagnostic modalities. While classified into sporadic, familial, iatrogenic, and variant forms, sporadic CJD remains the most prevalent, with a complex interplay of genetic, environmental, and stochastic factors contributing to its onset. The misfolding of cellular prion proteins (PrPC) into pathological conformers (PrPSc) serves as a hallmark event, instigating a cascade of neurotoxic processes, including protein aggregation, synaptic dysfunction, and neuronal death. Clinically, CJD manifests with a triad of progressive dementia, myoclonus, and characteristic electroencephalographic findings, presenting diagnostic challenges due to its heterogeneous symptomatology and overlap with other neurodegenerative conditions. However, advancements in biomarker identification, neuroimaging techniques, and cerebrospinal fluid analyses hold promise for enhancing early detection and differential diagnosis. Despite extensive research, therapeutic interventions for CJD remain limited, primarily focusing on symptomatic management and palliative care. Nevertheless, emerging strategies targeting prion propagation, immunotherapy, and gene editing offer potential avenues for disease modification and treatment. The profound impact of CJD on affected individuals, families, and healthcare systems underscores the imperative for continued research efforts aimed at unraveling its intricate pathophysiology and developing effective interventions to alleviate its burden.
2024-03-23 | Impact of FDA’s HCT/P ZIKV Recommendations on Cord Blood Unit Eligibility and Utilization in a Large Public Cord Blood Bank
Abstract Background Cord blood units (CBUs) that are ineligible for licensure due to incomplete compliance with FDA recommendations may be used for hematopoietic stem cell transplantation under urgent medical need and an Investigational Drug Application. The largest reason for CBU donor ineligibility is Zika virus (ZIKV) risk. The study’s objective was to analyze the impact of current FDA recommendations for ZIKA risk on a large public cord blood bank and propose updated recommendations. Methods We performed a retrospective analysis of Carolinas Cord Blood Bank (CCBB), an FDA licensed public CBB, using data from January 1, 2016 to November 21, 2023 and compared FDA recommendations for transfusion transmitted infections (TTI) for blood products and relevant communicable disease agents or diseases for human cell, tissue, or cellular or tissue-based products (HCT/Ps). Results CCBB: 9057 (84.3% licensed) CBUs were banked. 984/1682 (58.5%) of unlicensed CBUs had ZIKV risk. 22.0% of CBUs with ZIKV risk were from Hispanic parents, compared to 16.1% of all units. 31 of IND CBUs (11 due to ZIKV risk without reported ZIKV transmission) were safely infused. FDA Guidance: HCT/P ZIKV, HIV, and vCJD recommendations have not been updated since 2018 in contrast to FDA removal of ZIKV as a relevant TTI in 2021 and updating HIV and vCJD guidance related to TTI in 2023 and 2022, respectively. Discussion The FDA should consider new data to revise the HCT/P donor eligibility recommendations, which will increase the number of eligible HCT/P donors, and potentially improve access to therapies for a more diverse patient population.
2023-06-20 | NeuronalNdst1depletion accelerates prion protein clearance and slows neurodegeneration in prion infection
Abstract Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a major extracellular matrix component. HS facilitates fibril formation in vitro , yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for HS accelerating prion conversion in vitro . Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase, N-sulfotransferase), from neurons or astrocytes, we investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, affecting mice infected with extracellular, plaque-forming, but not membrane bound, prion strains. Live PET imaging revealed rapid clearance of prion protein monomers into the CSF in mice expressing unsulfated HS, further suggesting that HS sulfate groups hinder transit of extracellular prion monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme target to facilitate aggregate clearance. Author summary Prions cause a rapidly progressive neurologic disease and death with no curative treatment available. Prion aggregates accumulate exponentially in the brain in affected individuals triggering neuronal loss and neuroinflammation. Yet the additional molecules that facilitate aggregation are largely unknown, and their identification may lead to new therapeutic targets. We have found that prions in the brain preferentially bind to a highly sulfated endogenous polysaccharide, known as heparan sulfate (HS). Here we use genetically modified mice that express poorly sulfated neuron-derived HS, and infect mice with different prions strains. We find that the mice infected with a plaque-forming prion strain show a prolonged survival and fewer plaques compared to the controls. We also found that the prion protein was efficiently transported in the interstitial fluid in mice having poorly sulfated HS, suggesting that the prion protein is more readily cleared from the brain. Our study provides insight into how HS retains prion aggregates in the brain to accelerate disease and indicates the specific HS biosynthetic enzymes to target for enhancing protein clearance.
2023-06-19 | Human prion disease: molecular pathogenesis, and possible therapeutic targets and strategies.
Human prion diseases are heterogeneous, and often rapidly progressive, transmissible neurodegenerative disorders associated with misfolded prion protein (PrP) aggregation and self-propagation. Despite their rarity, prion diseases comprise a broad spectrum of phenotypic variants determined at the molecular level by different conformers of misfolded PrP and host genotype variability. Moreover, they uniquely occur in idiopathic, genetically determined, and acquired forms with distinct etiologies. This review provides an up-to-date overview of potential therapeutic targets in prion diseases and the main results obtained in cell and animal models and human trials. The open issues and challenges associated with developing effective therapies and informative clinical trials are also discussed. Currently tested therapeutic strategies target the cellular PrP to prevent the formation of misfolded PrP or to favor its elimination. Among them, passive immunization and gene therapy with antisense oligonucleotides against prion protein mRNA are the most promising. However, the disease's rarity, heterogeneity, and rapid progression profoundly frustrate the successful undertaking of well-powered therapeutic trials and patient identification in the asymptomatic or early stage before the development of significant brain damage. Thus, the most promising therapeutic goal to date is preventing or delaying phenoconversion in carriers of pathogenic mutations by lowering prion protein expression.
2022-10-05 | Genetic aspects of human prion diseases
Human prion diseases are rapidly progressive and fatal neurodegenerative conditions caused by a disease-causing isoform of the native prion protein. The prion protein gene ( PRNP ) encodes for the cellular prion protein, which is the biological substrate for prion disease transmission and neurotoxicity. Human prion diseases have three etiologies: sporadic, genetic, and acquired. PRNP polymorphisms and pathogenic variants play a large role in the frequency, age at onset, and clinicopathologic phenotype of prion diseases. Genetic prion diseases will be covered in detail and information necessary for clinical care, predictive genetic testing, and genetic counseling will be reviewed. Because the prion protein is necessary for transmission and neurotoxicity, many experimental treatments targeting its production are being investigated and hold potential promise as a disease modifying treatment for all forms of prion disease, including asymptomatic mutation carriers. This article will review genetic aspects of human prion disease and their influence on epidemiology, clinicopathologic phenotype, diagnostics, clinical management, and potential treatment approaches.
small molecules
2026-08-10 | Formic acid treatment drastically reduces sporadic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease infectivity in histological samples as tested in a high-sensitivity mouse bioassay.
Formic acid treatment is widely used in diagnostic neuropathology to reduce the infectivity of prion-containing tissues; however, quantitative in vivo evidence supporting its effectiveness under routine laboratory conditions remains limited. Here, we assessed the impact of formalin fixation and formic acid treatment on the infectivity of type 1 sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD) prions using highly sensitive transgenic mouse models overexpressing human-PrP M129 (Hu-Tg340) or bovine PrP (Bo-Tg110). Brain tissues were processed under conditions closely resembling standard histopathological workflows and tested as untreated, formalin-fixed or formalin-plus-formic-acid-treated inocula. Untreated samples produced short incubation times and full attack rates, whereas formalin fixation caused only a modest prolongation of incubation times. In contrast, formic acid treatment markedly extended incubation times and reduced attack rates for sCJD. Based on incubation-time interpolation, the estimated infectivity reductions were on the order of 4.4 log₁₀ for vCJD and 5 log₁₀ for sCJD. These estimates indicate a major reduction in infectious titre under the conditions tested, although residual infectivity was still detected. The findings support formic acid treatment as an important risk-reduction step in routine neuropathology workflows for the two prion strains examined.
2026-05-08 | Conjecture for a free radical epimerization process in Alzheimer, Parkinson, Lewy body, amyotrophic lateral sclerosis, progressive Supranuclear Palsy and Creutzfeldt Jakob diseases.
Brain protease-resistant misfolded proteins have been described in Alzheimer (AD), Parkinson (PD), Lewy Body (LBD), Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy (PSP) and Creutzfeldt Jakob (CJD) diseases. The role of free radicals in generating these protease resistant structures has been experimentally demonstrated in prion bovine spongiform encephalopathy (BSE), when manganese is substituted for copper (Cu), in bovine brain homogenates in reductive medium, while Cu protective effect against free radicals can be restored by Cu supplementation in oxidative medium. These facts can suggest a free radical-induced epimerization process in neuroprotein misfolding leading to the transformation of physiological L-amino acid brain proteins into abnormal D-structures which will be deposited in the brain as observed in neurodegenerative diseased brains. A blood Cu increase, not ceruloplasmin (CP) bound correlated with a Cu increase in the cerebrospinal fluid (CSF) and a Cu decrease in the brain have been described in AD, PD, ALS, or CJD. This indicates that following neuronal death, Cu might be expelled from brain proteins and subsequent to redistribution between brain, CSF and blood, it will result a brain Cu deficiency and a decrease in Cu brain protection against free radicals. In the aim of repairing this deficiency and slow down the neurodegenerative disease process, a brain Cu complexes vectorization through the blood-brain barrier might restore brain Cu homeostasis.
2025-08-06 | Molecular Insights into Prion Degradation in Creutzfeldt Jakob Disease’s Challenges and Future Directions: A Review
Creutzfeldt-Jakob Disease (CJD) is a rare, fatal neurodegenerative disorder characterized by the accumulation of misfolded prion proteins (PrP^Sc) in the central nervous system. This review explores the molecular dynamics of prion misfolding and its implications for disease progression, with a particular focus on cellular degradation pathways. Key proteolytic systems, including the ubiquitin-proteasome system and the autophagy-lysosome pathway, are critically analyzed for their roles in the clearance of PrP^Sc. Special emphasis is placed on lysosomal involvement, where autophagosomes fuse to form autolysosomes, facilitating the breakdown of pathogenic proteins. The interplay between proteases and molecular chaperones in maintaining protein homeostasis is also discussed. Neuropathologically, CJD is marked by spongiform alterations, neuronal loss, and gliosis. Clinically, the disease presents with rapidly progressive dementia, motor impairments, and psychiatric symptoms. The heterogeneity of CJD is addressed by outlining its sporadic, familial, iatrogenic, and variant subtypes. Recent advances in diagnostic techniques, including real-time quaking-induced conversion (RT-QuIC) in peripheral tissues, as well as the integration of machine learning tools and AI-assisted biomarker discovery, are highlighted. Emerging therapeutic strategies targeting proteolytic and lysosomal pathways are also reviewed, offering potential for future intervention in this currently untreatable disease.
2025-06-26 | Prion-induced ferroptosis is facilitated by RAC3.
Prions are infectious agents that initiate transmissible spongiform encephalopathies, causing devastating neuronal destruction in Creutzfeldt-Jakob and Kuru disease. Rapid cell death depends on presence of the endogenous prion protein PrPC, but its mechanistic contribution to pathogenesis is unclear. Here we investigate the molecular role of PrPC, reactive oxygen species and lipid metabolism in ferroptosis susceptibility, a regulated cell death process characterized by lipid peroxidation. We discover that elevated expression of the cellular prion PrPC creates a relaxed oxidative milieu that favors accumulation of unsaturated long-chain phospholipids responsible for ferroptotic death. This condition is sustained by the luminal protein glutathione peroxidase 8, which detoxifies reactive species produced by protein misfolding. Consequently, both PrPC and infectious Creutzfeldt-Jakob disease (CJD) prions trigger ferroptotic markers and sensitization. This lethality is further enhanced by RAC3, a small GTPase. Depletion of RAC3 is observed solely in pathologically afflicted cortices in CJD patients, revealing a synergistic modulation of lipids and reactive species that drives ferroptosis susceptibility. Together, the results show that PrPC initially suppresses oxidative stress, attenuates cellular defenses, and establishes a systemic vulnerability to the ferroptotic cascade. These results provide insight into the mechanism underlying regulation of ferroptosis in prion diseases and highlight potential therapeutic targets for diseases involving dysregulated cell death processes.
2025-06-20 | Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism.
Prion diseases are fatal, infectious, and incurable neurodegenerative conditions affecting humans and animals, caused by the misfolding of the cellular prion protein (PrPC) into its pathogenic isoform, PrPSc. In humans, sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent prion disease. Recently, we demonstrated that treatment with the FDA-approved anti-HIV drug efavirenz (EFV) significantly reduced PrPSc and extended survival of scrapie prion-infected mice. Among other effects, EFV activates the brain-specific cholesterol-metabolizing enzyme, CYP46A1, which converts cholesterol into 24S-hydroxycholesterol (24S-HC). However, drugs effective against scrapie prions often fail in human prion diseases, and a relation of the antiprion effects of EFV to CYP46A1 activation is not established. Thus, we evaluated EFV treatment in mice overexpressing human PrPC infected with human sCJD prions. Oral, low-dose EFV treatment starting at 30 or 130 days postinfection significantly slowed disease progression and extended their survival. At early clinical stage, we observed reduced PrPSc accumulation, decreased cholesterol and lipid droplet content, and elevated CYP46A1 and 24S-HC levels in EFV-treated mice. Overexpression of CYP46A1 in prion-infected neuronal cells reduced PrPSc levels and increased 24S-HC, indicating that antiprion effects of EFV correlate with CYP46A1 activation. These findings highlight EFV as a safe and efficacious therapeutic candidate for human prion diseases.
vaccines
2023-02-11 | Vaccines for prion diseases: a realistic goal?
Abstract Prion diseases are fatal infectious neurodegenerative disorders and prototypic conformational diseases, caused by the conformational conversion of the normal cellular prion protein (PrP C ) into the pathological PrP Sc isoform. Examples are scrapie in sheep and goat, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids, and Creutzfeldt–Jacob disease (CJD) in humans. There are no therapies available, and animal prion diseases like BSE and CWD can negatively affect the economy, ecology, animal health, and possibly human health. BSE is a confirmed threat to human health, and mounting evidence supports the zoonotic potential of CWD. CWD is continuously expanding in North America in numbers and distribution and was recently identified in Scandinavian countries. CWD is the only prion disease occurring both in wild and farmed animals, which, together with extensive shedding of infectivity into the environment, impedes containment strategies. There is currently a strong push to develop vaccines against CWD, including ones that can be used in wildlife. The immune system does not develop a bona fide immune response against prion infection, as PrP C and PrP Sc share an identical protein primary structure, and prions seem not to represent a trigger for immune responses. This asks for alternative vaccine strategies, which focus on PrP C -directed self-antibodies or exposure of disease-specific structures and epitopes. Several groups have established a proof-of-concept that such vaccine candidates can induce some levels of protective immunity in cervid and rodent models without inducing unwanted side effects. This review will highlight the most recent developments and discuss progress and challenges remaining.
2019-02-01 | Clinical trials of prion disease therapeutics
Prion-related encephalopathies or transmissible spongiform encephalopathies (TSEs) are a group of rare progressive neurodegenerative disorders that are invariably fatal with often only six months elapsing from diagnosis to patient death. This makes the development of effective therapeutic strategies challenging. Nonetheless, compounds have been identified in animal models of TSE that prolong survival and, in some instances, eradicate the disease. These have been tested in the clinic, although with modest or negative outcomes. While little progress has been made over the last decade, new findings that include the ability to identify prion aggregates at low levels in biological fluids and cells may lead to the development of early-stage biomarkers for TSE. An increased focus on immunotherapeutic approaches to TSE may result in the development of novel preventive approaches for TSE.
2016-04-14 | Methods and Protocols for Developing Prion Vaccines
Prion diseases denote a distinct form of infectivity that is based in the misfolding of a self-protein (PrPC) into a pathological, infectious conformation (PrPSc). Efforts to develop vaccines for prion diseases have been complicated by the potential dangers that are associated with induction of immune responses against a self-protein. As a consequence, there is considerable appeal for vaccines that specifically target the misfolded prion conformation. Such conformation-specific immunotherapy is made possible through the identification of vaccine targets (epitopes) that are exclusively presented as a consequence of misfolding. An immune response directed against these targets, termed disease-specific epitopes (DSEs), has the potential to spare the function of the native form of the protein while clearing, or neutralizing, the infectious isomer. Although identification of DSEs represents a critical first step in the induction of conformation-specific immune responses, substantial efforts are required to translate these targets into functional vaccines. Due to the poor immunogenicity that is inherent to self-proteins, and that is often associated with short peptides, substantial efforts are required to overcome tolerance-to-self and maximize the resultant immune response following DSE-based immunization. This often includes optimization of target sequences in terms of immunogenicity and development of effective formulation and delivery strategies for the associated peptides. Further, these vaccines must satisfy additional criteria from perspectives of specificity (PrPC vs. PrPSc) and safety (antibody-induced template-driven misfolding of PrPC). The emphasis of this report is on the steps required to translate DSEs into prion vaccines and subsequent evaluation of the resulting immune responses.
2014-09-30 | Prospects for safe and effective vaccines against prion diseases
Prion diseases are subacute neurodegenerative diseases that affect humans and animals. An abnormally folded isoform (PrPSc) of the host cellular prion protein is considered to constitute the major, if not sole, component of the infectious prion. The occurrence of variant Creutzfeldt–Jakob disease in humans most likely arose due to consumption of food contaminated with bovine spongiform encephalopathy prions. The demonstration that some prion infections may have the capacity to transmit to other species, especially humans, has focused attention on the development of safe and effective vaccines against these invariably fatal and currently incurable diseases. Although much effort has been invested in the development of safe and effective anti-PrP vaccines, many important issues remain to be resolved.
2013-10-20 | Evidence for Prion-Like Mechanisms in Several Neurodegenerative Diseases: Potential Implications for Immunotherapy
Transmissible spongiform encephalopathies (TSEs) are fatal, untreatable neurodegenerative diseases. While the impact of TSEs on human health is relatively minor, these diseases are having a major influence on how we view, and potentially treat, other more common neurodegenerative disorders. Until recently, TSEs encapsulated a distinct category of neurodegenerative disorder, exclusive in their defining characteristic of infectivity. It now appears that similar mechanisms of self-propagation may underlie other proteinopathies such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Huntington’s disease. This link is of scientific interest and potential therapeutic importance as this route of self-propagation offers conceptual support and guidance for vaccine development efforts. Specifically, the existence of a pathological, self-promoting isoform offers a rational vaccine target. Here, we review the evidence of prion-like mechanisms within a number of common neurodegenerative disorders and speculate on potential implications and opportunities for vaccine development.
antibodies
2026-06-30 | A scalable, dividing cell model for the robust propagation and quantification of human sporadic Creutzfeldt-Jakob disease prions.
Prion diseases represent a unique biological paradigm with mechanistic parallels to other neurodegenerative conditions like Alzheimer's and Parkinson's diseases. However, the study of human prion pathobiology and the development of effective therapeutics has been severely constrained by the inability to propagate human prions in dividing cells-forcing reliance on costly and slow animal bioassays. Here, we report the generation of EKV cells-a humanized cell model which supports the robust, indefinite propagation of sporadic Creutzfeldt-Jakob disease (sCJD) prions. We demonstrate that these cells replicate bona fide human prion infectivity in culture-cell lysates induce lethal neurodegeneration in humanized mice that is clinically and neuropathologically indistinguishable from inoculation with sCJD-infected brain tissue. We use EKV cells to develop the Human Prion Assay (HPA), which quantifies sCJD infectivity with sensitivity comparable to gold-standard mouse bioassay, while reducing the experimental timeline from years to weeks. Furthermore, we demonstrate that established sCJD infection can be cured by an anti-prion protein antibody, validating the system as a high-throughput platform for drug discovery. This model bridges a critical translational gap, offering a renewable alternative to animal bioassays, a paradigm to dissect the biology of human sCJD prion disease and screen for therapeutic agents.
2026-02-27 | Human Prion Disease: Pathogenesis, Diagnosis and Public Health.
Background: Prion diseases represent a group of rare, progressive, and invariably fatal neurodegenerative disorders. Their hallmark is the infectious nature of the misfolded prion protein (PrP^Sc), which propagates by inducing conformational changes in the physiological form (PrP^C). Despite advances in basic science, these disorders still pose major clinical and therapeutic challenges. Methods: A narrative review of the scientific literature was conducted across major biomedical databases, including PubMed, Scopus, Web of Science, and Google Scholar, covering publications up to January 2025. In addition, we describe an illustrative clinical case of a young patient with probable iatrogenic Creutzfeldt-Jakob disease following corneal transplantation, used to highlight diagnostic uncertainty and infection-control implications. Findings: Evidence confirms that PrP^Sc drives neurodegenerative processes and transmissibility, with phenotypic and genetic variants influencing clinical course and prognosis. From a diagnostic perspective, neuroimaging techniques and cerebrospinal fluid biomarkers have undergone substantial refinement, with RT-QuIC emerging as a highly specific and sensitive assay. Therapeutic options remain unsatisfactory: no treatment has shown a significant impact on survival. However, innovative strategies (including monoclonal antibodies, gene-based interventions, and modulation of PrP^C) represent promising avenues of investigation. Conclusions: Prion diseases remain an unresolved challenge at the intersection of neurology and infectious diseases. Earlier diagnosis through advanced biomarkers and continued development of targeted therapies are essential to improve patient management, while the persistence of iatrogenic cases underscores the ongoing relevance of surveillance and preventive strategies in clinical practice.
2022-04-25 | Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt-Jakob disease: evaluation of a first-in-human treatment programme.
Human prion diseases, including Creutzfeldt-Jakob disease (CJD), are rapidly progressive, invariably fatal neurodegenerative conditions with no effective therapies. Their pathogenesis involves the obligate recruitment of cellular prion protein (PrPC) into self-propagating multimeric assemblies or prions. Preclinical studies have firmly validated the targeting of PrPC as a therapeutic strategy. We aimed to evaluate a first-in-human treatment programme using an anti-PrPC monoclonal antibody under a Specials Licence. We generated a fully humanised anti-PrPC monoclonal antibody (an IgG4κ isotype; PRN100) for human use. We offered treatment with PRN100 to six patients with a clinical diagnosis of probable CJD who were not in the terminal disease stages at the point of first assessment and who were able to readily travel to the University College London Hospital (UCLH) Clinical Research Facility, London, UK, for treatment. After titration (1 mg/kg and 10 mg/kg at 48-h intervals), patients were treated with 80-120 mg/kg of intravenous PRN100 every 2 weeks until death or withdrawal from the programme, or until the supply of PRN100 was exhausted, and closely monitored for evidence of adverse effects. Disease progression was assessed by use of the Medical Research Council (MRC) Prion Disease Rating Scale, Motor Scale, and Cognitive Scale, and compared with that of untreated natural history controls (matched for disease severity, subtype, and PRNP codon 129 genotype) recruited between Oct 1, 2008, and July 31, 2018, from the National Prion Monitoring Cohort study. Autopsies were done in two patients and findings were compared with those from untreated natural history controls. We treated six patients (two men; four women) with CJD for 7-260 days at UCLH between Oct 9, 2018, and July 31, 2019. Repeated intravenous dosing of PRN100 was well tolerated and reached the target CSF drug concentration (50 nM) in four patients after 22-70 days; no clinically significant adverse reactions were seen. All patients showed progressive neurological decline on serial assessments with the MRC Scales. Neuropathological examination was done in two patients (patients 2 and 3) and showed no evidence of cytotoxicity. Patient 2, who was treated for 140 days, had the longest clinical duration we have yet documented for iatrogenic CJD and showed patterns of disease-associated PrP that differed from untreated patients with CJD, consistent with drug effects. Patient 3, who had sporadic CJD and only received one therapeutic dose of 80 mg/kg, had weak PrP synaptic labelling in the periventricular regions, which was not a feature of untreated patients with sporadic CJD. Brain tissue-bound drug concentrations across multiple regions in patient 2 ranged from 9·9 μg per g of tissue (SD 0·3) in the thalamus to 27·4 μg per g of tissue (1·5) in the basal ganglia (equivalent to 66-182 nM). Our academic-led programme delivered what is, to our knowledge, the first rationally designed experimental treatment for human prion disease to a small number of patients with CJD. The treatment appeared to be safe and reached encouraging CSF and brain tissue concentrations. These findings justify the need for formal efficacy trials in patients with CJD at the earliest possible clinical stages and as prophylaxis in those at risk of prion disease due to PRNP mutations or prion exposure. The Cure CJD Campaign, the National Institute for Health Research UCLH Biomedical Research Centre, the Jon Moulton Charitable Trust, and the UK MRC.
2021-08-18 | Exploring Drug and Antibody-Based Treatment Options for Creutzfeldt-Jakob Disease
Creutzfeldt-Jakob Disease (CJD) is a neurodegenerative disease characterized by mutant PrP prion proteins, which accumulates and impairs the function of wild-type PrPc proteins. The interaction of prion proteins with wild-type proteins converts the PrPc proteins to mutant PrP proteins. These mutant prion proteins lead to neural tissue degradation and other nervous system problems that can eventually lead to death. The use of antibodies to target and destroy prion proteins can be used to decrease PrP levels that can stop CJD progression. The binding affinities of different anti-PrP Fab antibodies are analyzed to determine which antibody best binds to PrP proteins and targets them for destruction. Through antibody-based targeting of prion proteins, potential treatment methods could be developed for CJD. In addition, the use of drugs, such as quinacrine and doxycycline, also show short-term effects in decreasing the progression of CJD. These drugs extend the average lifespan of tested subjects with CJD but also lead to the development of drug-resistant prion proteins that eventually cause the death of the subject affected by CJD.
2020-04-21 | Complement 3+-astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia.
Astrogliosis and activation of microglia are hallmarks of prion diseases in humans and animals. Both were viewed to be rather independent events in disease pathophysiology, with proinflammatory microglia considered to be the potential neurotoxic species at late disease stages. Recent investigations have provided substantial evidence that a proinflammatory microglial cytokine cocktail containing TNF-α, IL-1α and C1qa reprograms a subset of astrocytes to change their expression profile and phenotype, thus becoming neurotoxic (designated as A1-astrocytes). Knockout or antibody blockage of the three cytokines abolish formation of A1-astrocytes, therefore, this pathway is of high therapeutic interest in neurodegenerative diseases. Since astrocyte polarization profiles have never been investigated in prion diseases, we performed several analyses and could show that C3+-PrPSc-reactive-astrocytes, which may represent a subtype of A1-astrocytes, are highly abundant in prion disease mouse models and human prion diseases. To investigate their impact on prion disease pathophysiology and to evaluate their potential therapeutic targeting, we infected TNF-α, IL-1α, and C1qa Triple-KO mice (TKO-mice), which do not transit astrocytes into A1, with prions. Although formation of C3+-astrocytes was significantly reduced in prion infected Triple-KO-mice, this did not affect the amount of PrPSc deposition or titers of infectious prions. Detailed characterization of the astrocyte activation signature in thalamus tissue showed that astrocytes in prion diseases are highly activated, showing a mixed phenotype that is distinct from other neurodegenerative diseases and were therefore termed C3+-PrPSc-reactive-astrocytes. Unexpectedly, Triple-KO led to a significant acceleration of prion disease course. While pan-astrocyte and -microglia marker upregulation was unchanged compared to WT-brains, microglial homeostatic markers were lost early in disease in TKO-mice, pointing towards important functions of different glia cell types in prion diseases.
proteins
2025-04-30 | Abnormal Expression of Proteolytic Stress-Related Proteins and Protective Effect of Fibrinolytic Enzymes in Prion Diseases.
Prion diseases are fatal, irreversible, and infectious neurodegenerative diseases caused by proteinase K-resistant prion protein (PrPSc). Against PrPSc, several endogenous proteases involved in cellular degradation mechanisms can be activated to remove PrPSc. However, since PrPSc shows proteinase K resistance, we presumed that undegradable PrPSc induces positive feedback on the overactivation of the cellular degradation mechanisms and is correlated with proteolytic stress and exacerbation of the progression of prion diseases. We investigated the expression pattern of proteolytic stress-related proteins in the brains of ME7 scrapie-infected mice at 7 months postinfection and sporadic Creutzfeldt-Jakob disease (CJD) patients using western blotting and immunohistochemistry (IHC). In addition, we analyzed the 3D structure and binding complexes of prion protein (PrP) with nattokinase and lumbrokinase using in silico programs, including SWISS-MODEL and HawkDock. To fundamentally reduce proteolytic stress by the degradation of PrPSc, we performed an in vitro evaluation of the PrPSc degradation abilities of fibrinolytic enzymes, including nattokinase and lumbrokinase. Furthermore, we assessed the protective effects of nattokinase and lumbrokinase in ME7 scrapie-infected mice. We observed an abnormal accumulation of proteolytic stress-related proteins, including CD10, cathepsin B, cathepsin D, and matrix metalloproteinase 9 (MMP9), in the brains of ME7 scrapie-infected mice and sporadic CJD patients. In addition, we identified that nattokinase and lumbrokinase can stably bind to PrP. Furthermore, we identified significant in vitro degradation of PrPSc derived from ME7 scrapie-infected mice and sporadic CJD patients by nattokinase and lumbrokinase. Last, we found in vivo protective effects of nattokinase and lumbrokinase against prion disease in ME7 scrapie-infected mice. To the best of our knowledge, this is the first report on the identification of proteolytic stress-related novel potential biomarkers and the therapeutic potential of nattokinase and lumbrokinase for prion diseases.
2023-08-31 | Fibronectin: a natural barrier against prion infection
Abstract A distinctive signature of the prion diseases is the accumulation of the pathogenic isoform of the prion protein, PrP Sc , in the central nervous system of prion-affected humans and animals. PrP Sc is also found in peripheral tissues, raising concerns about the potential transmission of pathogenic prions through human food supplies and posing a significant risk to public health. Although muscle tissues are considered to contain levels of low prion infectivity, it has been shown that myotubes in culture efficiently propagate PrP Sc . Given the high consumption of muscle tissue, it is important to understand what factors could influence the establishment of a prion infection in muscle tissue. Here we used in vitro myotube cultures, differentiated from the C2C12 myoblast cell line (dC2C12), to identify factors affecting prion replication. A range of experimental conditions revealed that PrP Sc is tightly associated with proteins found in the systemic extracellular matrix (ECM), mostly fibronectin (FN). The interaction of PrP Sc with FN decreased prion infectivity, as determined by standard scrapie cell assay. Interestingly, the prion-resistant reserve cells in dC2C12 cultures displayed a FN-rich ECM while the prion-susceptible myotubes expressed FN at a low level. In agreement with the in vitro results, immunohistopathological analyses of tissues from sheep infected with natural scrapie demonstrated a prion susceptibility phenotype linked to an extracellular matrix with undetectable levels of FN. Conversely, PrP Sc deposits were not observed in tissues expressing FN. These data indicate that extracellular FN may act as a natural barrier against prion replication and that the extracellular matrix composition may be a crucial feature determining prion tropism in different tissues. Author summary Prion diseases are complex fatal neurodegenerative disorders caused by a misfolded form of the cellular protein PrP C (PrP Sc ). Due to the potential zoonotic transmission of these disorders through animal-based food intake, it is crucial to identify the tissues in which PrP Sc can accumulate and what might influence its tropism. Animal muscle (or meat) and related food products are highly consumed, raising concern of the involvement of muscle cells in prion replication. Muscle tissue from prion-affected animals contains low levels of infectivity and PrP Sc is mostly associated with nerve structures rather than myofibers, whereas C2C12 myotubes, a muscle-derived cell type, efficiently replicate prions in vitro and generate high levels of infectivity compared with other cell cultures. We demonstrate a fibronectin-mediated interference with prion infection in differentiated C2C12 cultures that correlates with the findings in tissues from naturally scrapie-infected animals. Our results suggest that extracellular matrix composition, specifically regarding the presence of fibronectin, might determine prion tropism and dissemination.
2023-07-14 | Different tau fibril types reduce prion level in chronically and de novo infected cells
Neurodegenerative diseases are often characterized by the codeposition of different amyloidogenic proteins, normally defining distinct proteinopathies. An example is represented by prion diseases, where the classical deposition of the aberrant conformational isoform of the prion protein (PrPSc) can be associated with tau insoluble species, which are usually involved in another class of diseases called tauopathies. How this copresence of amyloidogenic proteins can influence the progression of prion diseases is still a matter of debate. Recently, the cellular form of the prion protein, PrPC, has been investigated as a possible receptor of amyloidogenic proteins, since its binding activity with Aβ, tau, and α-synuclein has been reported, and it has been linked to several neurotoxic behaviors exerted by these proteins. We have previously shown that the treatment of chronically prion-infected cells with tau K18 fibrils reduced PrPSc levels. In this work, we further explored this mechanism by using another tau construct that includes the sequence that forms the core of Alzheimer's disease tau filaments in vivo to obtain a distinct fibril type. Despite a difference of six amino acids, these two constructs form fibrils characterized by distinct biochemical and biological features. However, their effects on PrPSc reduction were comparable and probably based on the binding to PrPC at the plasma membrane, inhibiting the pathological conversion event. Our results suggest PrPC as receptor for different types of tau fibrils and point out a role of tau amyloid fibrils in preventing the pathological PrPC to PrPSc conformational change.
2022-07-25 | Recombinant ovine prion protein can be mutated at position 136 to improve its efficacy as an inhibitor of prion propagation
Abstract Prion diseases are progressive neurodegenerative disorders with no effective therapeutics. A central event leading to the pathology in the diseases is the conversion of PrP C into PrP Sc and its accumulation in the central nervous system. Previous studies demonstrated that PrP C , recombinant PrP (rPrP) and PrP peptides can inhibit the formation of PrP Sc . Here, the effectiveness of ovine rPrP mutants at codon 136 and peptides derived from this region were assessed for their ability to inhibit PrP Sc replication, using protein misfolding cyclic amplification (PMCA). Based on a rPrP VRQ (rVRQ) genotype background (positions 136, 154 and 171) and mutations at position 136, the most effective inhibitors were V136R, V136K and V136P mutants, with IC50 values of 2–11 nM; activities up to 57 times more potent than rVRQ. rRRQ was also shown to inhibit a range of ruminant prion amplification reactions including with distinct prion strain seeds and substrate PRNP genotypes. The rRRQ was also shown to effectively protect Rov9 cells from scrapie infection when applied at 250 nM. The study demonstrates for the first time that the rPrP sequence can be mutated at sites known to be involved in prion disease susceptibility, to produce inhibitors with improved efficacy.
2022-04-13 | Serpin Signatures in Prion and Alzheimer’s Diseases
Serpins represent the most broadly distributed superfamily of proteases inhibitors. They contribute to a variety of physiological functions and any alteration of the serpin-protease equilibrium can lead to severe consequences. SERPINA3 dysregulation has been associated with Alzheimer's disease (AD) and prion diseases. In this study, we investigated the differential expression of serpin superfamily members in neurodegenerative diseases. SERPIN expression was analyzed in human frontal cortex samples from cases of sporadic Creutzfeldt-Jakob disease (sCJD), patients at early stages of AD-related pathology, and age-matched controls not affected by neurodegenerative disorders. In addition, we studied whether Serpin expression was dysregulated in two animal models of prion disease and AD.Our analysis revealed that, besides the already observed upregulation of SERPINA3 in patients with prion disease and AD, SERPINB1, SERPINB6, SERPING1, SERPINH1, and SERPINI1 were dysregulated in sCJD individuals compared to controls, while only SERPINB1 was upregulated in AD patients. Furthermore, we analyzed whether other serpin members were differentially expressed in prion-infected mice compared to controls and, together with SerpinA3n, SerpinF2 increased levels were observed. Interestingly, SerpinA3n transcript and protein were upregulated in a mouse model of AD. The SERPINA3/SerpinA3nincreased anti-protease activity found in post-mortem brain tissue of AD and prion disease samples suggest its involvement in the neurodegenerative processes. A SERPINA3/SerpinA3n role in neurodegenerative disease-related protein aggregation was further corroborated by in vitro SerpinA3n-dependent prion accumulation changes. Our results indicate SERPINA3/SerpinA3n is a potential therapeutic target for the treatment of prion and prion-like neurodegenerative diseases.
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2024-06-08 | CLINICALLY PROBABLE SPORADIC CREUTZFELDT JAKOB DISEASE (CJD)
Creutzfeldt-Jakob Disease (CJD) stands at the forefront of neurodegenerative disorders, characterized by rapid progression and devastating neurological deterioration. This review encapsulates the current understanding of CJD, encompassing its epidemiology, etiology, pathogenesis, clinical manifestations, and diagnostic modalities. While classified into sporadic, familial, iatrogenic, and variant forms, sporadic CJD remains the most prevalent, with a complex interplay of genetic, environmental, and stochastic factors contributing to its onset. The misfolding of cellular prion proteins (PrPC) into pathological conformers (PrPSc) serves as a hallmark event, instigating a cascade of neurotoxic processes, including protein aggregation, synaptic dysfunction, and neuronal death. Clinically, CJD manifests with a triad of progressive dementia, myoclonus, and characteristic electroencephalographic findings, presenting diagnostic challenges due to its heterogeneous symptomatology and overlap with other neurodegenerative conditions. However, advancements in biomarker identification, neuroimaging techniques, and cerebrospinal fluid analyses hold promise for enhancing early detection and differential diagnosis. Despite extensive research, therapeutic interventions for CJD remain limited, primarily focusing on symptomatic management and palliative care. Nevertheless, emerging strategies targeting prion propagation, immunotherapy, and gene editing offer potential avenues for disease modification and treatment. The profound impact of CJD on affected individuals, families, and healthcare systems underscores the imperative for continued research efforts aimed at unraveling its intricate pathophysiology and developing effective interventions to alleviate its burden.
2024-03-23 | Impact of FDA’s HCT/P ZIKV Recommendations on Cord Blood Unit Eligibility and Utilization in a Large Public Cord Blood Bank
Abstract Background Cord blood units (CBUs) that are ineligible for licensure due to incomplete compliance with FDA recommendations may be used for hematopoietic stem cell transplantation under urgent medical need and an Investigational Drug Application. The largest reason for CBU donor ineligibility is Zika virus (ZIKV) risk. The study’s objective was to analyze the impact of current FDA recommendations for ZIKA risk on a large public cord blood bank and propose updated recommendations. Methods We performed a retrospective analysis of Carolinas Cord Blood Bank (CCBB), an FDA licensed public CBB, using data from January 1, 2016 to November 21, 2023 and compared FDA recommendations for transfusion transmitted infections (TTI) for blood products and relevant communicable disease agents or diseases for human cell, tissue, or cellular or tissue-based products (HCT/Ps). Results CCBB: 9057 (84.3% licensed) CBUs were banked. 984/1682 (58.5%) of unlicensed CBUs had ZIKV risk. 22.0% of CBUs with ZIKV risk were from Hispanic parents, compared to 16.1% of all units. 31 of IND CBUs (11 due to ZIKV risk without reported ZIKV transmission) were safely infused. FDA Guidance: HCT/P ZIKV, HIV, and vCJD recommendations have not been updated since 2018 in contrast to FDA removal of ZIKV as a relevant TTI in 2021 and updating HIV and vCJD guidance related to TTI in 2023 and 2022, respectively. Discussion The FDA should consider new data to revise the HCT/P donor eligibility recommendations, which will increase the number of eligible HCT/P donors, and potentially improve access to therapies for a more diverse patient population.
2023-06-20 | NeuronalNdst1depletion accelerates prion protein clearance and slows neurodegeneration in prion infection
Abstract Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a major extracellular matrix component. HS facilitates fibril formation in vitro , yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for HS accelerating prion conversion in vitro . Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase, N-sulfotransferase), from neurons or astrocytes, we investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, affecting mice infected with extracellular, plaque-forming, but not membrane bound, prion strains. Live PET imaging revealed rapid clearance of prion protein monomers into the CSF in mice expressing unsulfated HS, further suggesting that HS sulfate groups hinder transit of extracellular prion monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme target to facilitate aggregate clearance. Author summary Prions cause a rapidly progressive neurologic disease and death with no curative treatment available. Prion aggregates accumulate exponentially in the brain in affected individuals triggering neuronal loss and neuroinflammation. Yet the additional molecules that facilitate aggregation are largely unknown, and their identification may lead to new therapeutic targets. We have found that prions in the brain preferentially bind to a highly sulfated endogenous polysaccharide, known as heparan sulfate (HS). Here we use genetically modified mice that express poorly sulfated neuron-derived HS, and infect mice with different prions strains. We find that the mice infected with a plaque-forming prion strain show a prolonged survival and fewer plaques compared to the controls. We also found that the prion protein was efficiently transported in the interstitial fluid in mice having poorly sulfated HS, suggesting that the prion protein is more readily cleared from the brain. Our study provides insight into how HS retains prion aggregates in the brain to accelerate disease and indicates the specific HS biosynthetic enzymes to target for enhancing protein clearance.
2023-06-19 | Human prion disease: molecular pathogenesis, and possible therapeutic targets and strategies.
Human prion diseases are heterogeneous, and often rapidly progressive, transmissible neurodegenerative disorders associated with misfolded prion protein (PrP) aggregation and self-propagation. Despite their rarity, prion diseases comprise a broad spectrum of phenotypic variants determined at the molecular level by different conformers of misfolded PrP and host genotype variability. Moreover, they uniquely occur in idiopathic, genetically determined, and acquired forms with distinct etiologies. This review provides an up-to-date overview of potential therapeutic targets in prion diseases and the main results obtained in cell and animal models and human trials. The open issues and challenges associated with developing effective therapies and informative clinical trials are also discussed. Currently tested therapeutic strategies target the cellular PrP to prevent the formation of misfolded PrP or to favor its elimination. Among them, passive immunization and gene therapy with antisense oligonucleotides against prion protein mRNA are the most promising. However, the disease's rarity, heterogeneity, and rapid progression profoundly frustrate the successful undertaking of well-powered therapeutic trials and patient identification in the asymptomatic or early stage before the development of significant brain damage. Thus, the most promising therapeutic goal to date is preventing or delaying phenoconversion in carriers of pathogenic mutations by lowering prion protein expression.
2022-10-05 | Genetic aspects of human prion diseases
Human prion diseases are rapidly progressive and fatal neurodegenerative conditions caused by a disease-causing isoform of the native prion protein. The prion protein gene ( PRNP ) encodes for the cellular prion protein, which is the biological substrate for prion disease transmission and neurotoxicity. Human prion diseases have three etiologies: sporadic, genetic, and acquired. PRNP polymorphisms and pathogenic variants play a large role in the frequency, age at onset, and clinicopathologic phenotype of prion diseases. Genetic prion diseases will be covered in detail and information necessary for clinical care, predictive genetic testing, and genetic counseling will be reviewed. Because the prion protein is necessary for transmission and neurotoxicity, many experimental treatments targeting its production are being investigated and hold potential promise as a disease modifying treatment for all forms of prion disease, including asymptomatic mutation carriers. This article will review genetic aspects of human prion disease and their influence on epidemiology, clinicopathologic phenotype, diagnostics, clinical management, and potential treatment approaches.
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