Human prion diseases

Transmissible spongiform encephalopathies (TSEs) are a family of neurodegenerative diseases characterized by their long incubation periods, progressive neurological changes, and spongiform appearance in the brain. There is much evidence to show that TSEs are caused by an isoform of the normal cellular surface prion protein PrPC. The normal function of PrPC is still unknown, but it exhibits properties of a cupro-protein, capable of binding up to six copper ions. There are two differing views on copper's role in prion diseases. While one view looks at the PrPC copper-binding as the trigger for conversion to PrPSc, the opposing viewpoint sees a lack of PrPC copper-binding resulting in the conformational change into the disease causing isoform. Manganese and zinc have been shown to interact with PrPC as well and have been found in abnormal levels in prion diseases. This review addresses the interaction between select trace elements and the PrPC.

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Metallic prions

Biochemical Society Symposium ◽

10.1042/bss0710193 ◽

2004 ◽

Vol 71 ◽

pp. 193-202 ◽

Cited By ~ 9

Author(s):

David R Brown

Keyword(s):

Prion Protein ◽

Binding Capacity ◽

Normal Function ◽

Transmissible Spongiform Encephalopathies ◽

Published Data ◽

Normal Brain ◽

Copper Binding ◽

Loss Of Function ◽

Spongiform Encephalopathies ◽

The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

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Transmissible Spongiform Encephalopathies Affecting Humans

ISRN Infectious Diseases ◽

10.5402/2013/387925 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11

Author(s):

Dudhatra G. B. ◽

Avinash Kumar ◽

Modi C. M. ◽

Awale M. M. ◽

Patel H. B. ◽

...

Keyword(s):

Neurological Disease ◽

Prion Diseases ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathies ◽

Neurologic Diseases ◽

Abnormal Protein ◽

Chain Reactions ◽

Personality Changes ◽

Incubation Periods ◽

The Brain

Transmissible spongiform encephalopathies (TSEs) or prion diseases are group of rare and rapidly progressive fatal neurologic diseases. The agents responsible for human prion diseases are abnormal proteins or prion that can trigger chain reactions causing normal proteins in the brain to change to the abnormal protein. These abnormal proteins are resistant to enzymatic breakdown, and they accumulate in the brain, leading to damage. TSEs have long incubation periods followed by chronic neurological disease and fatal outcomes, have similar pathology limited to the CNS including convulsions, dementia, ataxia, and behavioral or personality changes, and are experimentally transmissible to some other species.

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Oxford Textbook of Medicine ◽

10.1093/med/9780198746690.003.0599 ◽

2020 ◽

pp. 6109-6119

Author(s):

Simon Mead ◽

R.G. Will

Keyword(s):

Prion Disease ◽

Prion Diseases ◽

Mammalian Species ◽

Normal Function ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Spongiform Encephalopathies ◽

Distinct Disease ◽

Jakob Disease ◽

Disease Variant

Prion protein (for proteinacious infectious particle) is a membrane-associated glycoprotein present in all mammalian species. Its normal function is unknown, but in prion diseases (also known as transmissible spongiform encephalopathies) a misfolded polymer form of the protein, partially resistant to protease digestion, is deposited in the brain and associated—typically after long incubation periods—with neuronal dysfunction and death. Prion diseases have become the subject of intense scientific and public interest because they are caused by a biologically distinct disease mechanism and because of the implications for public health following the identification of a new human prion disease, variant Creutzfeldt–Jakob disease (vCJD), and the evidence that it is caused by the transmission to humans of a cattle prion disease, bovine spongiform encephalopathy (BSE).

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Backbone NMR assignments of the C-terminal domain of the human prion protein and its disease‐associated T183A variant

Biomolecular NMR Assignments ◽

10.1007/s12104-021-10005-y ◽

2021 ◽

Vol 15 (1) ◽

pp. 193-196

Author(s):

Máximo Sanz-Hernández ◽

Alfonso De Simone

Keyword(s):

Prion Protein ◽

Nmr Assignments ◽

Chemical Shifts ◽

Prion Diseases ◽

Random Coil ◽

Transmissible Spongiform Encephalopathies ◽

Globular Domain ◽

Structural Elements ◽

Spongiform Encephalopathies ◽

Human Prion Protein

AbstractTransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the misfolding and aggregation of the human prion protein (huPrP). Despite efforts into investigating the process of huPrP aggregation, the mechanisms triggering its misfolding remain elusive. A number of TSE-associated mutations of huPrP have been identified, but their role at the onset and progression of prion diseases is unclear. Here we report the NMR assignments of the C-terminal globular domain of the wild type huPrP and the pathological mutant T183A. The differences in chemical shifts between the two variants reveal conformational alterations in some structural elements of the mutant, whereas the analyses of secondary shifts and random coil index provide indications on the putative mechanisms of misfolding of T183A huPrP.

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Prions: Protein Aggregation and Infectious Diseases

Physiological Reviews ◽

10.1152/physrev.00006.2009 ◽

2009 ◽

Vol 89 (4) ◽

pp. 1105-1152 ◽

Cited By ~ 316

Author(s):

Adriano Aguzzi ◽

Anna Maria Calella

Keyword(s):

Protein Aggregation ◽

Prion Diseases ◽

Physiological Role ◽

Infectious Agent ◽

Normal Function ◽

Cellular Prion Protein ◽

Transmissible Spongiform Encephalopathies ◽

Pathological Features ◽

Spongiform Encephalopathies

Transmissible spongiform encephalopathies (TSEs) are inevitably lethal neurodegenerative diseases that affect humans and a large variety of animals. The infectious agent responsible for TSEs is the prion, an abnormally folded and aggregated protein that propagates itself by imposing its conformation onto the cellular prion protein (PrPC) of the host. PrPCis necessary for prion replication and for prion-induced neurodegeneration, yet the proximal causes of neuronal injury and death are still poorly understood. Prion toxicity may arise from the interference with the normal function of PrPC, and therefore, understanding the physiological role of PrPCmay help to clarify the mechanism underlying prion diseases. Here we discuss the evolution of the prion concept and how prion-like mechanisms may apply to other protein aggregation diseases. We describe the clinical and the pathological features of the prion diseases in human and animals, the events occurring during neuroinvasion, and the possible scenarios underlying brain damage. Finally, we discuss potential antiprion therapies and current developments in the realm of prion diagnostics.

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Prion disease

10.1093/med/9780199568741.003.0319 ◽

2018 ◽

Author(s):

Richard Knight

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Prion Diseases ◽

Human Diseases ◽

Brain Diseases ◽

Transmissible Spongiform Encephalopathies ◽

Structural Form ◽

Spongiform Encephalopathies ◽

Spongiform Change ◽

Neurodegenerative Pathology

Prion diseases (also known as transmissible spongiform encephalopathies (TSEs)) affect animals and humans, although only the human diseases will be discussed in this chapter. Despite TSEs having somewhat disparate causes and effects, there are unifying features: TSEs are brain diseases with neurodegenerative pathology, which is typically associated with spongiform change, and, most characteristically, there is tissue deposition of an abnormal structural form of the prion protein. Some of the TSEs are naturally acquired infections and, while others are not, they are potentially transmissible in certain circumstances.

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Prion Diseases and the Gastrointestinal Tract

Canadian Journal of Gastroenterology ◽

10.1155/2006/184528 ◽

2006 ◽

Vol 20 (1) ◽

pp. 18-24 ◽

Cited By ~ 21

Author(s):

Gwynivere A Davies ◽

Adam R Bryant ◽

John D Reynolds ◽

Frank R Jirik ◽

Keith A Sharkey

Keyword(s):

Nervous System ◽

Dendritic Cells ◽

Enteric Nervous System ◽

Prion Protein ◽

Cellular Prion Protein ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Gi Tract ◽

Spongiform Encephalopathies ◽

The Brain

The gastrointestinal (GI) tract plays a central role in the pathogenesis of transmissible spongiform encephalopathies. These are human and animal diseases that include bovine spongiform encephalopathy, scrapie and Creutzfeldt-Jakob disease. They are uniformly fatal neurological diseases, which are characterized by ataxia and vacuolation in the central nervous system. Alhough they are known to be caused by the conversion of normal cellular prion protein to its infectious conformational isoform (PrPsc) the process by which this isoform is propagated and transported to the brain remains poorly understood. M cells, dendritic cells and possibly enteroendocrine cells are important in the movement of infectious prions across the GI epithelium. From there, PrPscpropagation requires B lymphocytes, dendritic cells and follicular dendritic cells of Peyer’s patches. The early accumulation of the disease-causing agent in the plexuses of the enteric nervous system supports the contention that the autonomic nervous system is important in disease transmission. This is further supported by the presence of PrPscin the ganglia of the parasympathetic and sympathetic nerves that innervate the GI tract. Additionally, the lymphoreticular system has been implicated as the route of transmission from the gut to the brain. Although normal cellular prion protein is found in the enteric nervous system, its role has not been characterized. Further research is required to understand how the cellular components of the gut wall interact to propagate and transmit infectious prions to develop potential therapies that may prevent the progression of transmissible spongiform encephalopathies.

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Copper and prion diseases

Biochemical Society Transactions ◽

10.1042/bst0300742 ◽

2002 ◽

Vol 30 (4) ◽

pp. 742-745 ◽

Cited By ~ 16

Author(s):

D. R. Brown

Keyword(s):

Prion Protein ◽

Strong Evidence ◽

Prion Diseases ◽

Transmissible Spongiform Encephalopathies ◽

Normal Brain ◽

Spongiform Encephalopathies ◽

Metal Metabolism ◽

Jakob Disease ◽

Anti Oxidant ◽

Experimental Mouse

Transmissible spongiform encephalopathies are diseases of animals and humans that are also termed prion diseases. These diseases are linked together because a normal brain glycoprotein termed the prion protein is converted to a readily detectable protease-resistant isoform. There is now strong evidence to suggest that apart from this difference in resistance a major difference between the isoforms is that the normal prion protein binds copper and has an anti-oxidant function. Brains from Creutzfeldt-Jakob disease patients and brains from mice with experimental mouse scrapie have been shown to have changes in the levels of both copper and manganese. There is growing evidence that links prion diseases to disturbances of metal metabolism.

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Prion protein interconversions†

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2000.0765 ◽

2001 ◽

Vol 356 (1406) ◽

pp. 197-202 ◽

Cited By ~ 17

Author(s):

Byron Caughey

Keyword(s):

Neurodegenerative Diseases ◽

Prion Protein ◽

Prion Diseases ◽

Transmissible Spongiform Encephalopathies ◽

Biological Parameters ◽

Spongiform Encephalopathies ◽

Lead Compounds ◽

Resistant Form

The transmissible spongiform encephalopathies (TSEs), or prion diseases, remain mysterious neurodegenerative diseases that involve perturbations in prion protein (PrP) structure. This article summarizes our use of in vitro models to describe how PrP is converted to the disease–associated, protease–resistant form. These models reflect many important biological parameters of TSE diseases and have been used to identify inhibitors of the PrP conversion as lead compounds in the development of anti–TSE drugs.

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