The origin of bovine spongiform encephalopathy: the human prion disease hypothesis

ABSTRACT Bovine spongiform encephalopathy (BSE), the prion disease in cattle, was widely believed to be caused by only one strain, BSE-C. BSE-C causes the fatal prion disease named new variant Creutzfeldt-Jacob disease in humans. Two atypical BSE strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H, have been discovered in several countries since 2004; their transmissibility and phenotypes in humans are unknown. We investigated the infectivity and human phenotype of BASE strains by inoculating transgenic (Tg) mice expressing the human prion protein with brain homogenates from two BASE strain-infected cattle. Sixty percent of the inoculated Tg mice became infected after 20 to 22 months of incubation, a transmission rate higher than those reported for BSE-C. A quarter of BASE strain-infected Tg mice, but none of the Tg mice infected with prions causing a sporadic human prion disease, showed the presence of pathogenic prion protein isoforms in the spleen, indicating that the BASE prion is intrinsically lymphotropic. The pathological prion protein isoforms in BASE strain-infected humanized Tg mouse brains are different from those from the original cattle BASE or sporadic human prion disease. Minimal brain spongiosis and long incubation times are observed for the BASE strain-infected Tg mice. These results suggest that in humans, the BASE strain is a more virulent BSE strain and likely lymphotropic.

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Kuru, the First Human Prion Disease

Viruses ◽

10.3390/v11030232 ◽

2019 ◽

Vol 11 (3) ◽

pp. 232 ◽

Cited By ~ 12

Author(s):

Paweł Liberski ◽

Agata Gajos ◽

Beata Sikorska ◽

Shirley Lindenbaum

Keyword(s):

Electron Microscopy ◽

Confocal Microscopy ◽

Prion Disease ◽

Amyloid Plaques ◽

Human Medicine ◽

Spongiform Encephalopathy ◽

Biomedical Sciences ◽

Human Prion Disease ◽

History Of ◽

Jakob Disease

Kuru, the first human prion disease was transmitted to chimpanzees by D. Carleton Gajdusek (1923–2008). In this review, we summarize the history of this seminal discovery, its anthropological background, epidemiology, clinical picture, neuropathology, and molecular genetics. We provide descriptions of electron microscopy and confocal microscopy of kuru amyloid plaques retrieved from a paraffin-embedded block of an old kuru case, named Kupenota. The discovery of kuru opened new vistas of human medicine and was pivotal in the subsequent transmission of Creutzfeldt–Jakob disease, as well as the relevance that bovine spongiform encephalopathy had for transmission to humans. The transmission of kuru was one of the greatest contributions to biomedical sciences of the 20th century.

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First Report of the Potential Bovine Spongiform Encephalopathy (BSE)-Related Somatic Mutation E211K of the Prion Protein Gene (PRNP) in Cattle

International Journal of Molecular Sciences ◽

10.3390/ijms21124246 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4246 ◽

Cited By ~ 2

Author(s):

Sae-Young Won ◽

Yong-Chan Kim ◽

Byung-Hoon Jeong

Keyword(s):

Bovine Spongiform Encephalopathy ◽

Prion Protein ◽

Somatic Mutation ◽

Prion Disease ◽

In Silico ◽

Somatic Mutations ◽

Protein Gene ◽

Prnp Gene ◽

Spongiform Encephalopathy ◽

Prion Protein Gene

Bovine spongiform encephalopathy (BSE) is a prion disease characterized by spongiform degeneration and astrocytosis in the brain. Unlike classical BSE, which is caused by prion-disease-contaminated meat and bone meal, the cause of atypical BSE has not been determined. Since previous studies have reported that the somatic mutation in the human prion protein gene (PRNP) has been linked to human prion disease, the somatic mutation of the PRNP gene was presumed to be one cause of prion disease. However, to the best of our knowledge, the somatic mutation of this gene in cattle has not been investigated to date. We investigated somatic mutations in a total of 58 samples, including peripheral blood; brain tissue including the medulla oblongata, cerebellum, cortex, and thalamus; and skin tissue in 20 individuals from each breed using pyrosequencing. In addition, we estimated the deleterious effect of the K211 somatic mutation on bovine prion protein by in silico evaluation tools, including PolyPhen-2 and PANTHER. We found a high rate of K211 somatic mutations of the bovine PRNP gene in the medulla oblongata of three Holsteins (10% ± 4.4%, 28% ± 2%, and 19.55% ± 3.1%). In addition, in silico programs showed that the K211 somatic mutation was damaging. To the best of our knowledge, this study is the first to investigate K211 somatic mutations of the bovine PRNP gene that are associated with potential BSE progression.

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Mutant PrPSc Conformers Induced by a Synthetic Peptide and Several Prion Strains

Journal of Virology ◽

10.1128/jvi.78.4.2088-2099.2004 ◽

2004 ◽

Vol 78 (4) ◽

pp. 2088-2099 ◽

Cited By ~ 112

Author(s):

Patrick Tremblay ◽

Haydn L. Ball ◽

Kiyotoshi Kaneko ◽

Darlene Groth ◽

Ramanujan S. Hegde ◽

...

Keyword(s):

Prion Disease ◽

Synthetic Peptide ◽

Biologically Active ◽

Spongiform Encephalopathy ◽

Human Prion Disease ◽

Prion Strains ◽

Protease Digestion ◽

Brain Extracts ◽

Low Levels ◽

Prp Gene

ABSTRACT Gerstmann-Sträussler-Scheinker (GSS) disease is a dominantly inherited, human prion disease caused by a mutation in the prion protein (PrP) gene. One mutation causing GSS is P102L, denoted P101L in mouse PrP (MoPrP). In a line of transgenic mice denoted Tg2866, the P101L mutation in MoPrP produced neurodegeneration when expressed at high levels. MoPrPSc(P101L) was detected both by the conformation-dependent immunoassay and after protease digestion at 4°C. Transmission of prions from the brains of Tg2866 mice to those of Tg196 mice expressing low levels of MoPrP(P101L) was accompanied by accumulation of protease-resistant MoPrPSc(P101L) that had previously escaped detection due to its low concentration. This conformer exhibited characteristics similar to those found in brain tissue from GSS patients. Earlier, we demonstrated that a synthetic peptide harboring the P101L mutation and folded into a β-rich conformation initiates GSS in Tg196 mice (29). Here we report that this peptide-induced disease can be serially passaged in Tg196 mice and that the PrP conformers accompanying disease progression are conformationally indistinguishable from MoPrPSc(P101L) found in Tg2866 mice developing spontaneous prion disease. In contrast to GSS prions, the 301V, RML, and 139A prion strains produced large amounts of protease-resistant PrPSc in the brains of Tg196 mice. Our results argue that MoPrPSc(P101L) may exist in at least several different conformations, each of which is biologically active. Such conformations occurred spontaneously in Tg2866 mice expressing high levels of MoPrPC(P101L) as well as in Tg196 mice expressing low levels of MoPrPC(P101L) that were inoculated with brain extracts from ill Tg2866 mice, with a synthetic peptide with the P101L mutation and folded into a β-rich structure, or with prions recovered from sheep with scrapie or cattle with bovine spongiform encephalopathy.

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Prion disease: advances in diagnosis and treatment

Morecambe Bay Medical Journal ◽

10.48037/mbmj.v4i10.877 ◽

2005 ◽

Vol 4 (10) ◽

pp. 273-278

Author(s):

Steve Dealler

Keyword(s):

Bovine Spongiform Encephalopathy ◽

Prion Disease ◽

Transmissible Spongiform Encephalopathies ◽

The Political ◽

Spongiform Encephalopathy ◽

Potential Treatment ◽

Spongiform Encephalopathies ◽

Current State ◽

Jakob Disease ◽

Pentosan Polysulphate

Steve Dealler is a medical microbiologist with Morecambe Bay Hospitals NHS Trust. His work on on the diagnosis, epidemiology and potential treatment of transmissible spongiform encephalopathies has brought him inter-national recognition. He has been at the forefront of work on the epidemiology of human food containing the vector for bovine spongiform encephalopathy (BSE), and the development of prophylaxis against variant Creutzfeldt-Jakob disease (vCJD). He is currently working on a potential treatment, pentosan polysulphate. Here he describes the current state of knowledge in the battle against this devastating disease and the political inertia that frustrated earlier attempts to prevent the epidemic.

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Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2019

Communicable Diseases Intelligence ◽

10.33321/cdi.2020.44.56 ◽

2020 ◽

Vol 44 ◽

Author(s):

Christiane Stehmann ◽

Matteo Senesi ◽

Shannon Sarros ◽

Amelia McGlade ◽

Marion Simpson ◽

...

Keyword(s):

Prion Disease ◽

Disease Surveillance ◽

Prion Diseases ◽

Transmissible Spongiform Encephalopathy ◽

Annual Number ◽

Spongiform Encephalopathy ◽

Human Prion Disease ◽

Prospective Surveillance ◽

Jakob Disease ◽

Neuropathological Examination

Nationwide surveillance of Creutzfeldt-Jakob disease and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2019. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2019, 513 domestic CSF specimens were referred for 14-3-3 protein testing and 85 persons with suspected human prion disease were formally added to the national register. As of 31 December 2019, just under half (42 cases) of the 85 suspect case notifications remain classified as ‘incomplete’; 16 cases were excluded through either detailed clinical follow-up (3 cases) or neuropathological examination (13 cases); 20 cases were classified as ‘definite’ and seven as ‘probable’ prion disease. For 2019, sixty-three percent of all suspected human prion disease related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. Two possibly causal novel prion protein gene (PRNP) sequence variations were identified. Keywords: Creutzfeldt-Jakob disease, prion disease, transmissible spongiform encephalopathy, disease surveillance

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Retrospective Neuropathological Review of Prion Disease in UK Haemophilic Patients

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615387 ◽

1998 ◽

Vol 80 (12) ◽

pp. 909-911 ◽

Cited By ~ 45

Author(s):

James Ironside ◽

Jeanne Bell ◽

Paul Giangrande ◽

Christopher Ludlam ◽

Margaret M. Esiri ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Bovine Spongiform Encephalopathy ◽

Prion Protein ◽

Prion Disease ◽

Clotting Factor ◽

Spongiform Encephalopathy ◽

Post Mortem ◽

Blood Products ◽

Factor Concentrate ◽

Donor Source

SummaryIn 1996, the CJD surveillance unit in Edinburgh, UK described nvCJD which was thought to be the human equivalent of bovine spongiform encephalopathy (BSE). The identification of prion protein in the tonsil of an affected individual has raised the question of transmission of nvCJD via blood products. This study examines the post mortem brains of 33 patients who were treated with clotting factor concentrate of predominately UK donor source during the years 1962-1995. The brains were examined by conventional histological methods and also for the prion protein using monoclonal antibodies KG9 and 3F4. No evidence of spongiform encephalopathy was found and the immunocytochemistry was negative for PrP in all cases. It is concluded that, at present, there is no evidence for the transmission of nvCJD via clotting factor concentrate to patients with haemophilia.

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Study protocol for enhanced CJD surveillance in the 65+ years population group in Scotland: an observational neuropathological screening study of banked brain tissue donations for evidence of prion disease

BMJ Open ◽

10.1136/bmjopen-2019-033744 ◽

2019 ◽

Vol 9 (10) ◽

pp. e033744

Author(s):

Alexander Howard Peden ◽

Lovney Kanguru ◽

Diane L Ritchie ◽

Colin Smith ◽

Anna M Molesworth

Keyword(s):

Brain Tissue ◽

Prion Disease ◽

Age Of Onset ◽

Population Group ◽

Immunohistochemical Analysis ◽

Spongiform Encephalopathy ◽

Human Prion Disease ◽

Tissue Samples ◽

Jakob Disease ◽

The Uk

IntroductionCreutzfeldt-Jakob disease (CJD) is a human prion disease that occurs in sporadic, genetic and acquired forms. Variant CJD (vCJD) is an acquired form first identified in 1996 in the UK. To date, 178 cases of vCJD have been reported in the UK, most of which have been associated with dietary exposure to the bovine spongiform encephalopathy agent. Most vCJD cases have a young age of onset, with a median age at death of 28 years. In the UK, suspected cases of vCJD are reported to the UK National Creutzfeldt-Jakob Disease Research & Surveillance Unit (NCJDRSU). There is, however, a concern that the national surveillance system might be missing some cases of vCJD or other forms of human prion disease, particularly in the older population, perhaps because of atypical clinical presentation. This study aims to establish whether there is unrecognised prion disease in people aged 65 years and above in the Scottish population by screening banked brain tissue donated to the Edinburgh Brain Bank (EBB).MethodsNeuropathological screening of prospective and retrospective brain tissue samples is performed. This involves histopathological and immunohistochemical analysis and prion protein biochemical analysis. During the study, descriptive statistics are used to describe the study population, including the demographics and clinical, pathological and referral characteristics. Controlling for confounders, univariate and multivariate analyses will be used to compare select characteristics of newly identified suspect cases with previously confirmed cases referred to the NCJDRSU.Ethics and disseminationBrain tissue donations to EBB are made voluntarily by the relatives of patients, with consent for use in research. The EBB has ethical approval to provide tissue samples to research projects (REC reference 16/ES/0084). The findings of this study will be disseminated in meetings, conferences, workshops and as peer-reviewed publications.Trial registration numbers10/S1402/69 and 10/S1402/70

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Rapidly Progressing Sporadic Creutzfeldt-Jakob Disease Presenting as a Stroke

Case Reports in Neurology ◽

10.1159/000492613 ◽

2018 ◽

Vol 10 (3) ◽

pp. 261-265 ◽

Cited By ~ 1

Author(s):

Maxim Oliver ◽

Lisa Dyke ◽

Alex Rico ◽

Mario Madruga ◽

Jorge Parellada ◽

...

Keyword(s):

Prion Disease ◽

Neurological Disorders ◽

Hospice Care ◽

Clinical Suspicion ◽

Spongiform Encephalopathy ◽

Medical Procedures ◽

Human Prion Disease ◽

Progressive Dementia ◽

History Of ◽

Jakob Disease

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare, fatal human prion disease that is characterized by progressive dementia and neurologic degeneration. It can mimic multiple other neurological disorders, and a high index of clinical suspicion is necessary to make a diagnosis. A 74-year-old woman with a 3-month history of a stroke and progressive neurologic deterioration was found to have sCJD. She expired within a week of her diagnosis. Autopsy revealed spongiform encephalopathy consistent with prion disease, and genetic analysis revealed 129 polymorphism and no pathologic mutation, confirming the diagnosis of nonfamilial human prion disease. No pathologic evidence of a stroke was found. Awareness of the disease by clinicians is important not only at the time of initial presentation but also during the following months. Since there is no treatment, invasive medical procedures should be limited to only those that are required for either diagnosis or hospice care.

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A field on fire: The biochemistry of mad cows

The Biochemist ◽

10.1042/bio02704006 ◽

2005 ◽

Vol 27 (4) ◽

pp. 6-8

Author(s):

David R. Brown

Keyword(s):

Bovine Spongiform Encephalopathy ◽

Prion Protein ◽

Prion Disease ◽

Prion Diseases ◽

Human Diseases ◽

Spongiform Encephalopathy ◽

Related Disease ◽

Jakob Disease ◽

Sporadic Cjd

Prion diseases are neurodegenerative diseases1 that have been linked together because they may potentially have the same cause. These include the diseases scrapie of sheep and BSE (bovine spongiform encephalopathy) of cattle, and also several human diseases that include sporadic CJD (Creutzfeldt-Jakob) disease and a variety of inherited forms. The inherited forms of prion diseases are linked to mutations within the gene for the prion protein. Around 85% of all human cases of prion disease are sporadic CJD, which is a disease affecting people of around 60 years of age. The cause of this disease remains unknown. Unfortunately, the name of this disease causes some confusion, as it is similar to vCJD (variant CJD), a related disease of much younger people.

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