Key Points
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Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases of humans and many animal species that are caused by prions. The main constituent of prions is scrapie prion protein (PrPSc), an aggregated moiety of the host-derived membrane glycolipoprotein cellular prion protein (PrPC). Although PrPC is encoded by the host genome, prions were found to encipher many phenotypic TSE variants, known as prion strains.
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Prion strains are TSE isolates that, when inoculated into new hosts, consistently cause disease with specific characteristics, such as incubation period, patterns of PrPSc distribution and relative severity of spongiform changes in the brain (the lesion profile).The agent-specified information of prion strains is thought to be contained within distinct conformations of various PrPSc isotypes.
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Prions exert their destructive effects predominantly, if not exclusively, within the central nervous system. However, the direct cause of neurotoxicity remains unclear. PrPC is required for prion replication because mice that lack PrPC are resistant to prions. The presence of PrPC on neurons is a prerequisite for prion-induced neurotoxicity.
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A series of transgenic mice that express various prion protein mutants indicate that deletion of specific regions of PrPC can render it neurotoxic. This toxicity is modulated by co-expression of wild-type PrPC.
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Currently, there is no reagent allowing non-invasive, pre-mortem diagnosis of prion diseases. In view of recent unfortunate cases of Creutzfeldt–Jakob disease infection through blood transfusion, reliable, specific and, most importantly, sensitive reagents are urgently needed.
Abstract
Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases that are caused by prions and affect humans and many animal species. It is now widely accepted that the infectious agent that causes TSEs is PrPSc, an aggregated moiety of the host-derived membrane glycolipoprotein PrPC. Although PrPC is encoded by the host genome, prions themselves encipher many phenotypic TSE variants, known as prion strains. Prion strains are TSE isolates that, after inoculation into distinct hosts, cause disease with consistent characteristics, such as incubation period, distinct patterns of PrPSc distribution and spongiosis and relative severity of the spongiform changes in the brain. The existence of such strains poses a fascinating challenge to prion research.
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Acknowledgements
A.A. is supported by grants from the European Union (TSEUR and Immunoprion), the Swiss National Foundation, the National Center for Competence in Research on neural plasticity and repair, and the Ernst Jung Foundation. M.H. is supported by the Bonizzi–Theler Foundation and the Max Cloëtta Foundation. M.H. and M.P. are supported by the Foundation for Research at the Medical Faculty, University of Zürich, Switzerland.
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Glossary
- Transmissible spongiform encephalopathy
-
(TSE). A synonym for prion disease and a general term that refers to all diseases that are associated with the presence of prions in vacuolated central nervous system tissue. Prions from TSE-affected brains can be transmitted from one affected host to another host.
- Prion
-
An infectious agent with unconventional properties that causes TSE; it is an acronym for 'proteinaceous infectious particle'.
- vCJD
-
(Variant CJD). A type of CJD that is thought to result from the ingestion of beef products that are contaminated with bovine spongiform encephalopathy. The majority of vCJD cases occur in young individuals.
- Iatrogenic CJD
-
CJD transmission from human to human through medical mishaps (for example, transfusion of prion-infected blood).
- Familial CJD
-
Genetic prion diseases that are associated with mutations in one or more loci within the PRNP gene sequence.
- Sporadic CJD
-
The most common CJD, which occurs worldwide at a rate of one case per million people. It mostly affects older adults and the cause is unknown.
- 'Protein-only' hypothesis
-
This hypothesis proposes that the prion is devoid of informational nucleic acid and that the essential pathogenic component is a protein or glycoprotein.
- Scrapie prion protein
-
(PrPSc). An abnormal form of the mature PRNP gene product that is found in tissues of patients with TSE, defined as being partially resistant to proteinase-K digestion under standardized conditions. It is believed to differ from PrPC conformationally and is considered to be the main transmissible agent or prion.
- Cellular prion protein
-
(PrPC). The normally occurring form of the mature PRNP gene product, the presence of which is necessary, but not sufficient, for replication of the prion.
- Prion strain
-
A TSE isolate (or source of infection) that, upon inoculation into genetically identical hosts, causes prion disease with consistent characteristics. The agent-specified information in prion strains is thought to be contained in the distinct conformations of various PrPSc isotypes.
- Horizontal prion transmission
-
The spread of disease between individuals in a certain population or flock of animals. The cause of horizontal prion transmission in some cases (such as scrapie in sheep and chronic wasting disease in elk and deer) remains enigmatic.
- Bovine spongiform encephalopathy
-
(BSE). A TSE that primarily affects cattle, which is believed to be caused by animal feed that was contaminated with the prion agent of either scrapie or BSE. First identified in 1986 in the UK, it became an epidemic that affected hundreds of thousands of cattle in Europe.
- Chronic wasting disease
-
(CWD). A TSE of unknown origin that can be contracted by mule deer, white-tailed deer, Rocky Mountain elk and moose. CWD was identified in the early 1980s in the United States with a horizontal transmission of up to 20%.
- Scrapie
-
A TSE that affects sheep and goats. It has been known since at least the eighteenth century, hundreds of years before prions were first defined. Scrapie was shown to be transmissible 60 years ago.
- Lymphoreticular system
-
Part of the immune system. It is divided into primary (bone marrow and thymus) and secondary lymphoid tissues (spleen and lymph nodes).
- Ancillary genome
-
A putative (secondary) genome within the prion that might carry the information necessary for prion replication and disease phenotype. So far, all evidence points against the presence of an ancillary genome within the prion.
- Vacuolation
-
One of the main neuropathological hallmarks of prion diseases, which results from extensive neuronal loss leading to the occurrence of membrane-lined, optically empty intraneuronal organelles (termed vacuoles) within the brain.
- CJD types
-
Distinct isoforms of PrPSc that are associated with different CJD phenotypes. CJD types are biochemically distinguished by the different fragment sizes seen on western blots following treatment with proteinase K, as well as the ratio of PrPSc glycoforms and deposition patterns. In this article, we use the CJD classification that was proposed by Gambetti and colleagues.
- Amyloid-β
-
(Aβ). A hydrophobic peptide of 40–42 amino acids and the main component of amyloid plaques in the brains of patients with Alzheimer's disease. Aβ is a product of pathological cleavage of amyloid precursor protein (APP), a transmembrane protein that naturally occurs in the brain and other tissues of mammals.
- Neurotropic
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Prion strains that mainly attack the CNS. The prion infectivity of individuals who are infected with neurotropic prion strains is primarily contained within the CNS.
- Lymphotropic
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Prion strains that replicate in the lymphoreticular system before neuroinvasion. The prion infectivity of individuals who are infected with lymphotropic prion strains is found in peripheral lymphoid tissues and the CNS.
- Amyloid deposit
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A pathologic protein aggregate that occurs in the brains and other tissues of individuals suffering from amyloid or 'protein-misfolding' diseases. The main constituent of amyloid deposits is characteristic for each disease; for example, PrPSc in prion diseases and amyloid-β in Alzheimer's disease.
- Shmerling's disease
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A neurodegenerative syndrome that occurs in transgenic mice expressing N-terminally truncated PrPC, presenting with ataxia and cerebellar lesions. It can be reversed by the expression of a single allele of full-length PrPC.
- Neuropil
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The network made out of neuronal processes (axonal, dendritic and glial) within the grey matter of the CNS.
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Aguzzi, A., Heikenwalder, M. & Polymenidou, M. Insights into prion strains and neurotoxicity. Nat Rev Mol Cell Biol 8, 552–561 (2007). https://doi.org/10.1038/nrm2204
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DOI: https://doi.org/10.1038/nrm2204
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