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Handbook of Clinical Neurology 2018Currently all prion diseases are without effective treatment and are universally fatal. It is increasingly being recognized that the pathogenesis of many...
Currently all prion diseases are without effective treatment and are universally fatal. It is increasingly being recognized that the pathogenesis of many neurodegenerative diseases, such as Alzheimer disease (AD), includes "prion-like" properties. Hence, any effective therapeutic intervention for prion disease could have significant implications for other neurodegenerative diseases. Conversely, therapies that are effective in AD might also be therapeutically beneficial for prion disease. AD-like prion disease has no effective therapy. However, various vaccine and immunomodulatory approaches have shown great success in animal models of AD, with numerous ongoing clinical trials of these potential immunotherapies. More limited evidence suggests that immunotherapies may be effective in prion models and in naturally occurring prion disease. In particular, experimental data suggest that mucosal vaccination against prions can be effective for protection against orally acquired prion infection. Many prion diseases, including natural sheep scrapie, bovine spongiform encephalopathy, chronic wasting disease, and variant Creutzfeldt-Jakob disease, are thought to be acquired peripherally, mainly by oral exposure. Mucosal vaccination would be most applicable to this form of transmission. In this chapter we review various immunologically based strategies which are under development for prion infection.
Topics: Animals; Humans; Immunomodulation; Prion Diseases; Vaccination
PubMed: 29887149
DOI: 10.1016/B978-0-444-63945-5.00023-4 -
Biomedicine & Pharmacotherapy =... 1999A retroviral etiology might explain why amyloid plaque and/or spongiosis are or are not associated with neuronal death in prion diseases. While retroviral genes... (Review)
Review
A retroviral etiology might explain why amyloid plaque and/or spongiosis are or are not associated with neuronal death in prion diseases. While retroviral genes themselves may be responsible for neuronal death, a retrovirus may also cause mutations in cellular genes. Hence, the prion gene may be altered by a retrovirus in the same way as a cellular proto-oncogene is altered to produce an oncogene, either by transduction or by integration of the provirus in its vicinity. In both cases, the resulting abnormal prion protein, acting as a catalyst, may induce the formation of amyloid plaques. In addition, a wild type retrovirus may recombine to the vesicular stomatitis virus (VSV) to give rise to a pseudotyped retrovirus able to induce spongiosis. It is reported here that in scrapie, a blood monocytoid cell proliferates in vitro. If confirmed in other species, this raises the question of the potential link between prion disease and leukemia. Indeed neurovirulent strains of murine leukemia virus, a slow acting retrovirus, are known to induce spongiform encephalopathies. A preliminary attempt to purify reverse transcriptase by chromatography, using the classical protocol, failed because of the presence of a prion-like protein secreted by the blood mononuclear cells which stuck to the phosphocellulose column. Therefore, if a retrovirus is present in prion diseases, it would be evidenced only in animals developing the disease in the absence of prion protein. From this point of view, mice obtained in 1997 by the group of D. Dormont in France, offer a unique opportunity to test the retroviral hypothesis.
Topics: Animals; Humans; Preleukemia; Prion Diseases; Proto-Oncogene Mas; Retroviridae; Retroviridae Infections
PubMed: 10221168
DOI: 10.1016/s0753-3322(99)80060-2 -
Journal of Neurology, Neurosurgery, and... Jul 2005Prions are infectious pathogens principally composed of abnormal forms of a protein encoded in the host genome. They cause lethal neurodegenerative conditions including... (Review)
Review
Prions are infectious pathogens principally composed of abnormal forms of a protein encoded in the host genome. They cause lethal neurodegenerative conditions including CJD, GSS, and kuru in humans and scrapie and bovine spongiform encephalopathy in domestic animals. Remarkably, distinct strains of prions occur despite absence of an agent-specific genome: misfolded proteins themselves may encode strain diversity--with wide implications in biology. The arrival of variant CJD, and the experimental confirmation that it is caused by infection with BSE-like prions, has focussed research on early diagnosis and treatment. Recent advances lead to considerable optimism that effective human therapies may now be developed. While several drugs have been tried in small numbers of patients, there is no clear evidence of efficacy of any agent and controlled clinical trials are urgently needed. Importantly, there is increasing recognition that fundamental processes involved in prion propagation--seeded aggregation of misfolded host proteins--are of far wider significance, not least in understanding the commoner neurodegenerative diseases that pose such a major and increasing challenge for healthcare in an ageing population.
Topics: Animals; Clinical Trials as Topic; Early Diagnosis; Gene Expression; Humans; Mammals; Prion Diseases; Prions; Protein Conformation; Protein Isoforms; Species Specificity
PubMed: 15965195
DOI: 10.1136/jnnp.2004.048660 -
Neurocase Jun 2023Alzheimer's Disease (AD) is the most common cause of dementia, although multiple pathologies are found in nearly half of the cases with clinically diagnosed AD. Prion...
Alzheimer's Disease (AD) is the most common cause of dementia, although multiple pathologies are found in nearly half of the cases with clinically diagnosed AD. Prion diseases, such as Creutzfeldt-Jakob disease (CJD), are rare causes of dementia and typically manifest as a rapidly progressive dementia, where symptom onset to dementia most often occurs over the course of months. In this brief report, we describe a patient's typically progressive dementia with a precipitous decline at the end of their life who, on neuropathological evaluation, was found to have multiple neurodegenerative proteinopathies as well as spongiform encephalopathy due to CJD. This case of unsuspected CJD highlights a rare, but epidemiologically important, cause of sudden decline in well-established neurodegenerative dementias.
Topics: Humans; Creutzfeldt-Jakob Syndrome; Dementia; Prion Diseases; Male; Aged; Female; Disease Progression; Mixed Dementias
PubMed: 38687122
DOI: 10.1080/13554794.2024.2346990 -
Microbes and Infection Oct 2000Prion propagation is associated with accumulation of a conformational isomer of host encoded cellular prion protein, PrP(C). Solution structures of several mammalian... (Review)
Review
Prion propagation is associated with accumulation of a conformational isomer of host encoded cellular prion protein, PrP(C). Solution structures of several mammalian PrPs have now been reported and they have stimulated a significant advance in our understanding of the folding dynamics of PrP. Studies on recombinant PrP have shown the polypeptide chain is able to adopt different topologies in different solvent conditions. Concomitantly, advances in the analysis of the abnormal isoform, PrP(Sc), have expanded our knowledge on the molecular basis of prion strains and have done much to reinforce the protein-only hypothesis of prion replication.
Topics: Animals; Brain; Mice; Models, Biological; Prion Diseases; Prions; Protein Conformation; Structure-Activity Relationship
PubMed: 11099931
DOI: 10.1016/s1286-4579(00)01299-5 -
Therapeutic Delivery May 2013Therapeutic trials utilizing animal models of prion disease have explored a variety of compounds and a number of approaches with varying success, including several... (Review)
Review
Therapeutic trials utilizing animal models of prion disease have explored a variety of compounds and a number of approaches with varying success, including several immunotherapeutic strategies, such as passive immunization through the delivery of viruses carrying nucleic acid inserts encoding prion protein-specific immunoglobulin. Targeted, organ-specific cellular production of therapeutic proteins is a relatively unexplored approach in the treatment of neurodegeneration despite many successful experimental outcomes in animal models and human trials of other diseases of the CNS. Emphasizing studies utilizing mouse models of disease, this review outlines developments and limitations of immunological approaches to the treatment of prion diseases. In addition, the authors discuss the potential of an experimental therapeutic strategy, utilizing hybridoma cells injected directly into the CNS to establish long-term production of anti-prion antibodies in vivo within the organ associated with the greatest pathogenic change in prion disease, the brain.
Topics: Animals; Brain; Cell- and Tissue-Based Therapy; Disease Models, Animal; Humans; Hybridomas; Immunotherapy; Mice; Prion Diseases; Prions
PubMed: 23647278
DOI: 10.4155/tde.13.30 -
Communications Biology Nov 2023Infectious prions consist of PrP, a misfolded, aggregation-prone isoform of the host's prion protein. PrP assemblies encode distinct biochemical and biological...
Infectious prions consist of PrP, a misfolded, aggregation-prone isoform of the host's prion protein. PrP assemblies encode distinct biochemical and biological properties. They harbor a specific profile of PrP species, from small oligomers to fibrils in different ratios, where the highest infectivity aligns with oligomeric particles. To investigate the impact of PrP aggregate complexity on prion propagation, biochemical properties, and disease pathogenesis, we fractionated elk prions by sedimentation velocity centrifugation, followed by sub-passages of individual fractions in cervidized mice. Upon first passage, different fractions generated PrP with distinct biochemical, biophysical, and neuropathological profiles. Notably, low or high molecular weight PrP aggregates caused different clinical signs of hyperexcitability or lethargy, respectively, which were retained over passage, whereas other properties converged. Our findings suggest that PrP quaternary structure determines an initial selection of a specific replication environment, resulting in transmissible features that are independent of PrP biochemical and biophysical properties.
Topics: Mice; Animals; Prion Diseases; Prions; Prion Proteins
PubMed: 37964018
DOI: 10.1038/s42003-023-05541-3 -
Biochemical Society Transactions Apr 2010Synaptic dysfunction is a key early process in many neurodegenerative diseases, but how this ultimately leads to neuronal loss is not clear. In health, there is ongoing... (Review)
Review
Synaptic dysfunction is a key early process in many neurodegenerative diseases, but how this ultimately leads to neuronal loss is not clear. In health, there is ongoing remodelling of synapses and spines in the adult brain: their elimination and formation are continual physiological processes fundamental to learning and memory. But in neurodegenerative disease, including prion disease, lost synapses are not replaced, and their loss is followed by neuronal death. These two processes are separately regulated, with mechanistic, spatial and temporal segregation of the respective death routines of synapses and cell bodies. Mice with prion disease can be cured at the stage of early synaptic dysfunction, when they have reversible impairments at neurophysiological, behavioural and morphological levels. Critically, reversing synaptic dysfunction at this stage of disease rescues neurons, preventing its otherwise inevitable progression to synapse loss and cell death. These findings call for a deeper analysis of the mechanisms underlying neurotoxicity at the synapse, and have important implications for the therapy of prion and other neurodegenerative disorders.
Topics: Adult; Animals; Humans; Mice; Models, Biological; Neurodegenerative Diseases; Neurons; Prion Diseases; Recovery of Function; Synapses
PubMed: 20298207
DOI: 10.1042/BST0380482 -
Arkhiv Patologii 1999Human prion disorders include Kuru, Creutzfeld-Jakob disease (CJD), Gerstman-Straussler-Scheinkler syndrome (GSS), fatal familial insomnia (FFI) and prion protein... (Review)
Review
Human prion disorders include Kuru, Creutzfeld-Jakob disease (CJD), Gerstman-Straussler-Scheinkler syndrome (GSS), fatal familial insomnia (FFI) and prion protein cerebral amyloid angiopathy (PrPCAA). Prion diseases manifest as infections, genetic and sporadic disorders. In these diseases an abnormal form of the host's protein, prion protein protease-resistant (PrPres), is essential for pathogenic process. Host protein, prion protein protease-sensitive (PrPsen) in humans is encoded by a single copy gene (PRNP) located in the short arm of chromosome 20. To date, 19 different mutations in PRNP have been found that cause inherited prion disease. In these diseases PrPsen undergoes conformational changes involving a shift from alpha-helix to beta-sheet structures. This conversion is important for PrP-amyloidogenesis which occurs to the highest degree in GSS, while it is less frequently seen in other prion diseases. Pathomorphologically, amyloidogenesis in the brain is characterized by formation of PrPres conglomerates, diffuse homogeneous deposits and pleomorphic fibrillar amyloid plaques. The neurotoxic activity of PrPres and its fragments supports the causal relationship between PrPres deposits and neuropathological events in prion diseases. Congo-red and certain sulfated glycans potently inhibit PrPres formation. This raises the potential of therapeutic strategies for the treatment of these diseases.
Topics: Amyloidosis; Animals; Brain Diseases; Creutzfeldt-Jakob Syndrome; Endopeptidases; Humans; Kuru; Mutation; Periodicity; Prion Diseases
PubMed: 10412591
DOI: No ID Found -
Scientific Reports Oct 2023Prion disease is a fatal neurodegenerative disorder characterized by accumulation of an abnormal prion protein (PrPSc) in the central nervous system. To identify PrPSc...
Prion disease is a fatal neurodegenerative disorder characterized by accumulation of an abnormal prion protein (PrPSc) in the central nervous system. To identify PrPSc aggregates for diagnostic purposes, pathologists use immunohistochemical staining of prion protein antibodies on tissue samples. With digital pathology, artificial intelligence can now analyze stained slides. In this study, we developed an automated pipeline for the identification of PrPSc aggregates in tissue samples from the cerebellar and occipital cortex. To the best of our knowledge, this is the first framework to evaluate PrPSc deposition in digital images. We used two strategies: a deep learning segmentation approach using a vision transformer, and a machine learning classification approach with traditional classifiers. Our method was developed and tested on 64 whole slide images from 41 patients definitively diagnosed with prion disease. The results of our study demonstrated that our proposed framework can accurately classify WSIs from a blind test set. Moreover, it can quantify PrPSc distribution and localization throughout the brain. This could potentially be extended to evaluate protein expression in other neurodegenerative diseases like Alzheimer's and Parkinson's. Overall, our pipeline highlights the potential of AI-assisted pathology to provide valuable insights, leading to improved diagnostic accuracy and efficiency.
Topics: Humans; Prion Proteins; Artificial Intelligence; Prion Diseases; Brain; Machine Learning
PubMed: 37853094
DOI: 10.1038/s41598-023-44782-4