Advancing Prion Science Guidance for the National Prion Research Program (2004) / Chapter Skim
Currently Skimming:
2 Prion Diseases: An Overview
2 Prion Diseases: An Overview
Pages 39-59
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 39... ...
In fact, the outbreaks of bovine spongiform encephalopathy (BSE) and variant Creutzfel~t-Takob disease (vCTD)
|
From page 40... ...
Rather, the purpose of this report is to call for additional research especially studies of the fundamental molecular structures and mechanisms related to TSEs so that disparate views may converge and ac Vance prlon science. ORIGINS AND DEVELOPMENT OF PRION SCIENCE The identification of a previously unknown malady in the Fore Tribe of Papua New Guinea drew international attention to the group of brain-wasting diseases called TSEs.
|
From page 41... ...
The disease was transmitted successfully to a chimpanzee, which first displayed clinical signs after a 1 3-month incubation period, providing more evidence that spongiform encephalopathies are transmissible (Gibbs et al., 1968~. These studies and observations generated a groundswell of interest in discovering the nature of the infectious agent or agents that caused scrapie and kuru.
|
From page 42... ...
In 1982, Prusiner asserted that the infectious agent of scrapie was either a protein or a small nucleic acid surrounded by a tightly packed protein (Prusiner, 1982, 1999~. He called this infectious agent a prion, which stands for "small, proteinaceous infectious particles that are resistant to inactivation by most procedures that modify nucleic acids" (Prusiner, 1982:141~.
|
From page 43... ...
This anchor is added to the molecule when amino acids 231-253, known as the GPI signal sequence, are removed during a process called transamidation. Two cystine amino acid residues form a tight bond in the C-terminus region.
|
From page 44... ...
Familial Creutzieldt- Genetic 1924b Jakob disease Fatal familial insomnia Genetic 1986C (FFI) Gerstmann-Straussler- Genetic 19363 Scheinker disease Kuru Iatrogenic Creutzieldt Jakob disease Variant Creutzieldt Jakob disease (vCJD)
|
From page 45... ...
Then the carbohydrates and the GPI anchor are added to the protein, and it migrates to the cell surface membrane. Conversion of prpC to PrPSc Mature human prpC polypeptide consists of amino acids 23-230.
|
From page 46... ...
In a demonstration of the pivotal role of normal prion proteins in the progression of TSEs, mice in which prpC expression was knocked out or ablated remained healthy after infection with prions (Bueler et al., 19931. It is widely hypothesized that one or more socalled chaperone molecules may play a role in the conversion of prpC to PrPSc (Chernoff et al., 1995; Telling et al., 19951.
|
From page 47... ...
Unlike PrPC, PrPSc is resistant to proteolytic degradation and can accumulate within lysosomes, on the cell surface, or in extracellular deposits, such as rod-shaped fibrils or amyloid plaques. These abnormal accumulations are ultimately neurotoxic.
|
From page 48... ...
Studies using the agent of transmissible mink encephalopathy in hamsters showed differences in clinical presentation and PrPSc glycoform patterns by prion strain (Bessen and Marsh, 1992~. Recently, the use of selected inbred and transgenic mice to characterize prion strains has led to important insights, including the idea that a similar strain causes both BSE and vCTD (Bruce et al., 1997; Scott et al., 19991.
|
From page 49... ...
Neuropathological examination of the sick cattle's brains revealed abnormal, microscopic vacuoles and fibrils, much like the spongiform characteristics of scrapie and kuru. A team of veterinary scientists at the United Kingdom's Ministry of Agriculture reported in 1987 that the new disease strongly resembled the so-called unconventional viral-agent encephalopathies previously observed in sheep and the Fore people, so the scientists named the disease bovine spongiform encephalopathy (Welis et al., 1987~.
|
From page 50... ...
so o .' o o o o ~ o ~ cO cO cd .o o ~ s cd Q ~ O .,' S O . _ o CM o o CM o saseo ~o ~aqtunN o o O O o .
|
From page 51... ...
is appropriate only for shortterm forecasts (2003~. Moreover, they note, the epidemic's future is clouded by many unknowns: the uncertain incubation period of vCTD in people who are heterozygous at PRNP codon 129 or are homozygous for valine; the possibility that subgroups within the methionine-homozygous population have different incubation periods; the possibility that there are unidentified strains of BSE that incubate longer in humans than does the known strain; and the possibility of human-to-human transmission through blood products, surgical instruments, or tissue transplants.
|
From page 52... ...
The fitted quadratic trend appears within its 95 percent confidence limits and has been adjusted for the time delay between onset and diagnosis.
|
From page 53... ...
The nature of these signs led biologists to name the illness chronic wasting disease. The most striking and consistent pathological features observed by the early CWD researchers were nerve cell degeneration and widespread microscopic vacuoles in the neurons of the brain and spinal cord trademarks of the spongiform encephalopathies previously described in sheep, goats, and humans.
|
From page 54... ...
Moreover, since PrPSc and prpC have identical amino acid sequences, the existence of a prior-specific antibody has not been confirmed to date, and infected individuals do not exhibit a prior-specific immune response. In addition, prions replicate sluggishly in existing cell culture systems and incubate for several months to several years in animal models, limiting the pace of research.
|
From page 55... ...
Sensitive, specific TSE diagnostics would help protect people and animals from fatal prion infections in the absence of prophylactics and treatments. Given that there are few tools to inactivate priors, the ability to test blood and other tissues for prions would help prevent the inadvertent transmission of vCTD by blood transfusion or organ transplantation, provided that there is actually any infectious agent to be detected in blood or the organs used for transplantation (see Chapter 51.
|
From page 56... ...
1999. Prion protein and the transmissible spongiform encephalopathy diseases.
|
From page 57... ...
2003. The economic consequences of bovine spongiform encephalopathy and foot and mouth disease outbreaks in the United States.
|
From page 58... ...
1999. Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans.
|
From page 59... ...
1980. Chronic wasting disease of captive mule deer: a spongiform encephalopathy.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.