References cited were from the Creutzfeldt-Jakob disease bibliography, Department of Pathology, University of Melbourne, maintained by the Australian National Creutzfeldt-Jakob Disease Registry (http://data.path.unimelb.edu.au/RIS/RISWEB.ISA [accessed Sept 22, 2003]). Generally, references chosen fulfilled one or more of the following criteria: major breakthroughs in transmissible spongiform encephalopathy research; first reports of key observations, if replicated; largest studies reported to
SeminarTransmissible spongiform encephalopathies
Section snippets
Molecular biology of PrP and pathogenesis of TSE
The pathogenesis of TSE is linked to simultaneous expression of normal PrP (PrPc or PrPsen) and accumulation of structurally aberrant, protease-resistant, conformers (PrPres).5 These protein conformers have identical primary structures (aminoacid sequences) but differ at a higher structural level such as folding. PrPres is a generic term, denoting abnormal conformers associated with, for example, scrapie (PrPSc) and CJD (PrPCJD). Nosologically, therefore, TSE should be grouped with other
Normal PrP
PrPc(figure 1) is encoded by PRNP, a small, single-copy, housekeeping gene on chromosome 20, which is expressed at highest levels in neurons.7 The gene has only three exons and the entire open reading frame is in one exon. The human PrPc protein is synthesised as a 253 aminoacid polypeptide chain from which the first 22 aminoacids (signal peptide) are cleaved shortly after translation commences. Post-translational processing adds a C-terminal glycosylphosphatidylinositol (GPI)-anchor at residue
Generation of PrPres from PrPc
The primary aminoacid sequences of PrPc and PrPres are exactly the same. PrPres is only detectable in the context of disease, developing through post-translational modifications that involve conformational rather than covalent change. Furthermore, the amounts of PrP mRNA transcripts in the brain do not rise as disease progresses.7 Laboratory data, including repeated failure to detect a conventional infectious agent, have consolidated the protein-only (prion) hypothesis, that PrPres constitutes
PrPres fragments and glycotypes
Variations in tertiary structure of PrPres probably correlate with differing surface exposures of the protein, and account for differences in cleavage sites with protease digestion. Proteinase K digestion of PrPres removes a variable number of N-terminal aminoacids (up to around residue 90), and the resulting fragment shows a relative mobility of 27–30 kDa on western blots (PrP27–30).5 Two nomenclatures have been used to describe protease-resistant PrPres fragments in non-familial CJD. The
Is PrPres solely responsible for neurodegeneration and infectivity?
20 years have elapsed since hamster-adapted scrapie infectivity was shown to copurify with a protein of 27–30 kDa (PrP27–30), and the term prion was coined to describe a proteinaceous infectious particle resistant to inactivation procedures that modify nucleic acids.1, 5 Considerable data now lend support to the primacy of PrPres in disease pathogenesis and transmission. Nevertheless, some in-vitro and animal models of TSE prompt uncertainty.
Infectivity and neurodegeneration probably have
Sporadic CJD
Sporadic CJD typically presents as a rapidly progressive dementia, often accompanied by cerebellar ataxia and myoclonus, with death in an akinetic-mute state after a median of 4–5 months. Around 90% of patients die within 12 months, although survival for more than 2 years is recognised.48, 49 Mean age at onset is about 60 years, with little difference in age-adjusted sex incidence. By striking contrast with the incidence of Alzheimer's and Parkinson's diseases, which rises sharply with age,
Chronic subclinical infection
The notion of latent or subclinical infection in TSE has been revived98 by studies with mice.86, 87, 99, 100 A striking feature is the extended survival and apparent good health (for up to hundreds of days) despite chronic infection. Brains of these asymptomatic animals carry high titres of infectivity similar to those of mice dying from terminal disease, with typical spongiform changes sometimes seen histologically and PrPres recorded on western blots.86, 87, 99, 101, 102 Such findings
Sporadic CJD and epidemics of TSE
CJD can arise de novo as a result of mutations in PRNP, be secondary to horizontal (case-to-case) transmission, or most usually (around 85% of total) be without apparent cause (sporadic). Sporadic disease has an annual incidence of only 1·0–1·5 per million,48, 103, 104 although unexplained rates up to 3·9 per million have been reported for Switzerland.105 Such an unusual incidence may not simply be a result of enhanced ascertainment but could relate to exposure to bovine spongiform
Decontamination issues
The infectious agents of TSE resist conventional sterilisation and decontamination methods,117 especially on stainless-steel surfaces.118 Mild (especially non-ionic) detergents, chlorine dioxide, alcohols, potassium permanganate, hydrogen peroxide, aldehydes, ultraviolet irradiation, and ethylene oxide are ineffective. Autoclaving at 134/r°C for at least 18 min in a porous load device or for about 1 h at standard autoclave temperatures in a gravity displacement steriliser, or soaking
Therapeutic approaches
No proven treatment for human or non-human TSE exists. Research tends to focus on compounds postulated to prevent—directly or indirectly—misfolding of PrPc to PrPres, diminish neurotoxicity, or promote clearance of pre-existing PrPres. Compounds studied include polyanions, sulfonated dyes, tetrapyrroles, polyene antibiotics, branched polyamines, cysteine protease inhibitors, acridine derivatives, phenothiazines, suramine, synthetic peptides,120 and small interfering RNA duplexes, which have
Search strategy and selection criteria
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A new variant of Creutzfeldt-Jakob disease in the UK
Lancet
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A cellular gene encodes scrapie PrP 27-30 protein
Cell
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NMR characterization of the full-length recombinant murine prion protein, mPrP(23-231)
FEBS Lett
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Copper binding to the octarepeats of the prion protein. Affinity, specificity, folding, and cooperativity: insights from circular dichroism
J Biol Chem
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Ablation of the metal ion-induced endocytosis of the prion protein by disease-associated mutation of the octarepeat region
Curr Biol
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Reversibility of scrapie inactivation is enhanced by copper
J Biol Chem
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Mutant prion proteins are partially retained in the endoplasmic reticulum
J Biol Chem
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Mutant PrP is delayed in its exit from the endoplasmic reticulum, but neither wild-type nor mutant PrP undergoes retrotranslocation prior to proteasomal degradation
J Biol Chem
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Reversibility of scrapie-associated prion protein aggregation
J Biol Chem
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Mice devoid of PrP are resistant to scrapie
Cell
(1993)