Human Prion Diseases

2018 ◽  
pp. 159-171
Author(s):  
James W. Ironside
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Neuronal Loss ◽  
Human Prion Disease ◽  
Clinical Genetic ◽  
Jakob Disease ◽  
Biochemical Approach ◽  
Protein Isoform ◽  
The Brain

Human prion diseases include idiopathic, genetic, and acquired disorders. Heterogeneous clinicopathologic features make diagnosis challenging. Accurate diagnosis requires a combined clinical, neuropathologic, genetic, and biochemical approach. Neuropathologic assessment is performed following autopsy in most cases. The brain is sampled and studied by tinctorial stains and immunohistochemistry for disease-associated form of the prion protein. Unfixed frozen brain tissue is retained for Western blot analysis of protease-resistant prion protein isoform and for DNA extraction to sequence the prion protein gene. Assessment of spongiform change, gliosis neuronal loss, and accumulation of disease-associated prion protein in the brain can help to determine major categories of human prion disease. Additional clinical, genetic, and biochemical data allow diagnosis and subclassification into disease subtypes, particularly in sporadic Creutzfeldt–Jakob disease. Neuropathology continues to play a role in the recognition and understanding of the expanding spectrum of human prion disease and identification of disease variants that may emerge in the future.

The neuroepidemiology of human prion disease

2020 ◽  
pp. 367-378
Author(s):  
Patrick JM Urwin ◽  
Anna M Molesworth
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Prion Protein Gene ◽  
Human Prion Disease ◽  
Disease States ◽  
Jakob Disease ◽  
The Central Nervous System ◽  
Sporadic Disease

Human prion diseases comprise a number of rare and fatal neurodegenerative conditions that result from the accumulation in the central nervous system of an abnormal form of a naturally occurring protein, called the prion protein. The diseases occur in genetic, sporadic, and acquired forms: genetic disease is associated with mutations in the prion protein gene (PRNP); sporadic disease is thought to result from a spontaneous protein misfolding event; acquired disease results from transmission of infection from an animal or another human. The potential transmissibility of the prion in any of these forms, either in disease states or during the incubation period, has implications for public health. Here we focus on Creutzfeldt-Jakob Disease (CJD), including variant Creutzfeldt-Jakob Disease (vCJD), although we will also discuss other forms of human prion disease.

scholarly journals Genetic human prion disease modelled in PrP transgenic Drosophila

2017 ◽  
Vol 474 (19) ◽  
pp. 3253-3267 ◽  
Author(s):  
Alana M. Thackray ◽  
Alzbeta Cardova ◽  
Hanna Wolf ◽  
Lydia Pradl ◽  
Ina Vorberg ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Principal Component ◽  
Site Directed Mutagenesis ◽  
Host Protein ◽  
Therapeutic Interventions ◽  
Proteinase K ◽  
Human Prion Disease ◽  
Transgenic Drosophila

Inherited human prion diseases, such as fatal familial insomnia (FFI) and familial Creutzfeldt–Jakob disease (fCJD), are associated with autosomal dominant mutations in the human prion protein gene PRNP and accumulation of PrPSc, an abnormal isomer of the normal host protein PrPC, in the brain of affected individuals. PrPSc is the principal component of the transmissible neurotoxic prion agent. It is important to identify molecular pathways and cellular processes that regulate prion formation and prion-induced neurotoxicity. This will allow identification of possible therapeutic interventions for individuals with, or at risk from, genetic human prion disease. Increasingly, Drosophila has been used to model human neurodegenerative disease. An important unanswered question is whether genetic prion disease with concomitant spontaneous prion formation can be modelled in Drosophila. We have used pUAST/PhiC31-mediated site-directed mutagenesis to generate Drosophila transgenic for murine or hamster PrP (prion protein) that carry single-codon mutations associated with genetic human prion disease. Mouse or hamster PrP harbouring an FFI (D178N) or fCJD (E200K) mutation showed mild Proteinase K resistance when expressed in Drosophila. Adult Drosophila transgenic for FFI or fCJD variants of mouse or hamster PrP displayed a spontaneous decline in locomotor ability that increased in severity as the flies aged. Significantly, this mutant PrP-mediated neurotoxic fly phenotype was transferable to recipient Drosophila that expressed the wild-type form of the transgene. Collectively, our novel data are indicative of the spontaneous formation of a PrP-dependent neurotoxic phenotype in FFI- or CJD-PrP transgenic Drosophila and show that inherited human prion disease can be modelled in this invertebrate host.

scholarly journals Central and peripheral pathology of kuru: pathological analysis of a recent case and comparison with other forms of human prion disease

2008 ◽  
Vol 363 (1510) ◽  
pp. 3755-3763 ◽  
Author(s):  
Sebastian Brandner ◽  
Jerome Whitfield ◽  
Ken Boone ◽  
Anderson Puwa ◽  
Catherine O'Malley ◽  
...  
Keyword(s):  
Prion Protein ◽  
Human Prion Disease ◽  
Peripheral Tissues ◽  
Prion Strain ◽  
Pathological Analysis ◽  
Lymphoreticular Tissue ◽  
Jakob Disease ◽  
Strain Type ◽  
Few Data ◽  
The Brain

While the neuropathology of kuru is well defined, there are few data concerning the distribution of disease-related prion protein in peripheral tissues. Here we report the investigation of brain and peripheral tissues from a kuru patient who died in 2003. Neuropathological findings were compared with those seen in classical (sporadic and iatrogenic) Creutzfeldt–Jakob disease (CJD) and variant CJD (vCJD). The neuropathological findings of the kuru patient showed all the stereotypical changes that define kuru, with the occurrence of prominent PrP plaques throughout the brain. Lymphoreticular tissue showed no evidence of prion colonization, suggesting that the peripheral pathogenesis of kuru is similar to that seen in classical CJD rather than vCJD. These findings now strongly suggest that the characteristic peripheral pathogenesis of vCJD is determined by prion strain type alone rather than route of infection.

scholarly journals Large-scale lipidomic profiling identifies novel potential biomarkers for prion diseases and highlights lipid raft-related pathways

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Yong-Chan Kim ◽  
Junbeom Lee ◽  
Dae-Weon Lee ◽  
Byung-Hoon Jeong
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Large Scale ◽  
Right Hemisphere ◽  
Prion Diseases ◽  
Lipid Extraction ◽  
Transmissible Spongiform Encephalopathies ◽  
Pathway Enrichment Analysis ◽  
The Brain ◽  
Potential Biomarkers

AbstractPrion diseases are transmissible spongiform encephalopathies induced by the abnormally-folded prion protein (PrPSc), which is derived from the normal prion protein (PrPC). Previous studies have reported that lipid rafts play a pivotal role in the conversion of PrPC into PrPSc, and several therapeutic strategies targeting lipids have led to prolonged survival times in prion diseases. In addition, phosphatidylethanolamine, a glycerophospholipid member, accelerated prion disease progression. Although several studies have shown that prion diseases are significantly associated with lipids, lipidomic analyses of prion diseases have not been reported thus far. We intraperitoneally injected phosphate-buffered saline (PBS) or ME7 mouse prions into mice and sacrificed them at different time points (3 and 7 months) post-injection. To detect PrPSc in the mouse brain, we carried out western blotting analysis of the left hemisphere of the brain. To identify potential novel lipid biomarkers, we performed lipid extraction on the right hemisphere of the brain and liquid chromatography mass spectrometry (LC/MS) to analyze the lipidomic profiling between non-infected mice and prion-infected mice. Finally, we analyzed the altered lipid-related pathways by a lipid pathway enrichment analysis (LIPEA). We identified a total of 43 and 75 novel potential biomarkers at 3 and 7 months in prion-infected mice compared to non-infected mice, respectively. Among these novel potential biomarkers, approximately 75% of total lipids are glycerophospholipids. In addition, altered lipids between the non-infected and prion-infected mice were related to sphingolipid, glycerophospholipid and glycosylphosphatidylinositol (GPI)-anchor-related pathways. In the present study, we found novel potential biomarkers and therapeutic targets of prion disease. To the best of our knowledge, this study reports the first large-scale lipidomic profiling in prion diseases.

Enzymatic detergent treatment protocol that reduces protease-resistant prion protein load and infectivity from surgical-steel monofilaments contaminated with a human-derived prion strain

2007 ◽  
Vol 88 (10) ◽  
pp. 2905-2914 ◽  
Author(s):  
Victoria A. Lawson ◽  
James D. Stewart ◽  
Colin L. Masters
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Disease Transmission ◽  
Prion Diseases ◽  
Medical Instrument ◽  
Treatment Protocol ◽  
Infectious Agent ◽  
Surgical Instruments ◽  
Prion Strain ◽  
Jakob Disease

The unconventional nature of the infectious agent of prion diseases poses a challenge to conventional infection control methodologies. The extraneural tissue distribution of variant and sporadic Creutzfeldt–Jakob disease has increased concern regarding the risk of prion disease transmission via general surgical procedures and highlighted the need for decontamination procedures that can be incorporated into routine processing. In this study, the ability of preparations of enzymatic medical instrument cleaners to reduce the infectivity associated with a rodent-adapted strain of human prion disease, previously reported to be resistant to decontamination, was tested. Efficient degradation of the disease-associated prion protein by enzymatic cleaning preparations required high treatment temperatures (50–60 °C). Standard decontamination methods (1 M NaOH for 1 h or autoclaving at 134 °C for 18 min) reduced infectivity associated with the human-derived prion strain by less than 3 log10 LD50. In contrast, a 30 min treatment with the optimized enzymatic cleaning preparation protocols reduced infectivity by more than 3 log10 LD50 and when used in conjunction with autoclave cycles eliminated detectable levels of infectivity. The development of prion decontamination procedures that are compatible with routine cleaning and sterilization of medical and surgical instruments may reduce the risk of the transmission of prion disease in general surgery.

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

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

scholarly journals Skin RT-QuIC Assays are More Sensitive than CSF RT-QuIC in Prion Detection for Chinese Probable Sporadic Creutzfeldt-Jakob Disease

2020 ◽  
Author(s):  
Kang Xiao ◽  
Xue-Hua Yang ◽  
Wei Zhou ◽  
Cao Chen ◽  
Brian S Appleby ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Prion Disease ◽  
Preliminary Data ◽  
High Sensitivity ◽  
Definite Diagnosis ◽  
Human Prion Disease ◽  
Diagnostic Potential ◽  
Jakob Disease ◽  
The Brain ◽  
Skin Specimen

Abstract BackgroundThe definite diagnosis of human sporadic Creutzfeldt-Jakob disease (sCJD) largely depends on postmortem neuropathology and PrPSc detection in the brain. The development of prion RT-QuIC of cerebrospinal fluid (CSF) samples makes it possible for premortem diagnosis for sCJD. However the diagnostic potential of RT-QuIC of skin specimen for probable sCJD is not well researched. This study is to evaluate the diagnostic potential of RT-QuIC of skin specimen in human prion diseases.MethodsWe collected the paired skin and CSF samples from 29 recruited alive patients referred to Chinese CJD surveillance center, including 12 probable sCJD, 9 non-CJD, 3 genetic prion disease (gPrD) and 5 cases whose diagnoses still pending. The samples were subjected to RT-QuIC assays using recombinant hamster PrP protein rHaPrP90-231 as the substrate.ResultsAll 12 probable sCJD patients, 4 pending, and 1 T188K genetic CJD (gCJD) cases showed positive prion-seeding activity, while all 9 non-CJD patients were negative. CSF RT-QuIC positive seeding activity was only observed in 5 probable sCJD patients.ConclusionsOur preliminary data indicate high sensitivity and specificity of skin RT-QuIC in prion detection for Chinese probable sCJD and highlight that skin prion-seeding activity is a reliable biomarker for premortem diagnosis of human prion disease.

scholarly journals Ethanolamine Is a New Anti-Prion Compound

2021 ◽  
Vol 22 (21) ◽  
pp. 11742
Author(s):  
Keiji Uchiyama ◽  
Hideyuki Hara ◽  
Junji Chida ◽  
Agriani Dini Pasiana ◽  
Morikazu Imamura ◽  
...  
Keyword(s):  
Drinking Water ◽  
Oral Administration ◽  
Prion Protein ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Mouse Neuroblastoma ◽  
Conformational Conversion ◽  
The Brain ◽  
Cells Cultured

Prion diseases are a group of fatal neurodegenerative disorders caused by accumulation of proteinaceous infectious particles, or prions, which mainly consist of the abnormally folded, amyloidogenic prion protein, designated PrPSc. PrPSc is produced through conformational conversion of the cellular isoform of prion protein, PrPC, in the brain. To date, no effective therapies for prion diseases have been developed. In this study, we incidentally noticed that mouse neuroblastoma N2a cells persistently infected with 22L scrapie prions, termed N2aC24L1-3 cells, reduced PrPSc levels when cultured in advanced Dulbecco’s modified eagle medium (DMEM) but not in classic DMEM. PrPC levels remained unchanged in prion-uninfected parent N2aC24 cells cultured in advanced DMEM. These results suggest that advanced DMEM may contain an anti-prion compound(s). We then successfully identified ethanolamine in advanced DMEM has an anti-prion activity. Ethanolamine reduced PrPSc levels in N2aC24L1-3 cells, but not PrPC levels in N2aC24 cells. Also, oral administration of ethanolamine through drinking water delayed prion disease in mice intracerebrally inoculated with RML scrapie prions. These results suggest that ethanolamine could be a new anti-prion compound.

scholarly journals Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2018

2019 ◽  
Vol 43 ◽  
Author(s):  
Christine Stehmann ◽  
Matteo Senesi ◽  
Victoria Lewis ◽  
Mairin Ummi ◽  
Marion Simpson ◽  
...  
Keyword(s):  
Prion Disease ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
Annual Number ◽  
Human Prion Disease ◽  
Prospective Surveillance ◽  
Surveillance Period ◽  
Spongiform Encephalopathies ◽  
Jakob Disease ◽  
Neuropathological Examination

Nationwide surveillance of human prion diseases (also known as transmissible spongiform encephalopathies), the most common being Creutzfeldt-Jakob disease (CJD), is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR), based at the University of Melbourne. 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 relation to pre-mortem diagnostics, the delineation of new disease subtypes and a heightened awareness of prion diseases in health care settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR from 1 January to 31 December 2018. 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 2018, 465 domestic CSF specimens were referred for 14-3-3 protein testing and 78 persons with suspected human prion disease were formally added to the national register. The majority of the 78 suspect case notifications remain as of 31 December 2018 classified as “incomplete” (42 cases), while eleven cases were excluded by either detailed clinical follow-up (one case) or neuropathological examination (ten cases); 15 cases were classified as “definite” and ten as “probable” prion disease. Sixty-two percent of all suspected human prion disease related deaths underwent neuropathological examination. No cases of variant CJD were confirmed.

Prion Diseases

2017 ◽  
Author(s):  
James A. Mastrianni ◽  
Joshuae G. Gallardo
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Protein Gene ◽  
Prion Diseases ◽  
Prion Protein Gene ◽  
Secondary Transmission ◽  
Jakob Disease

Prion diseases are transmissible fatal neurodegenerative disorders resulting from the accumulation of misfolded prion protein. Although primarily sporadic diseases, 5% to 10% result from a mutation of the prion protein gene (PRNP), and less than 1% occur from exposure to prions. The current family of prion diseases includes Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), fatal insomnia (FI), variant CJD (vCJD), and variably protease-sensitive prionopathy (VPSPr). Kuru is a disease of historical interest that was transmitted through cannibalistic rituals. Iatrogenic CJD (iCJD) is the result of secondary transmission of prion disease from contaminated biologicals.

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