Elsevier

The Lancet

Volume 363, Issue 9402, 3 January 2004, Pages 51-61
The Lancet

Seminar
Transmissible spongiform encephalopathies

https://doi.org/10.1016/S0140-6736(03)15171-9Get rights and content

Summary

Nosologically, transmissible spongiform encephalopathies (TSE or prion diseases) should be grouped with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, which are all caused by toxic gain of function of an aberrant form of a constitutively expressed protein. Failure to clear these proteins from the brain induces neuronal dysfunction. Transmissibility is the property that separates TSE from other neurodegenerative diseases, and this property seems to reside within the structure of the abnormal protein. The human phenotypic range of these encephalopathies includes Creutzfeldt-Jakob disease and its variant form, kuru, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia. Notwithstanding the generally low incidence of TSE and their limited infectiousness, major epidemics such as bovine spongiform encephalopathy and kuru arise in situations where intraspecies recycling of the abnormal protein is sustained. Moreover, evidence of chronic subclinical infection in animals offers insights into pathogenesis and prompts re-evaluation of the notion of species barriers and present infection control measures. Since case-to-case transmission is the only known mechanism underlying epidemics of TSE, potential reservoirs of infectivity in the tails of epidemics need continued vigilance.

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

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

References (128)

  • Sánchez-ValleR et al.

    14-3-3 Protein isoforms and atypical patterns of the 14-3-3 assay in the diagnosis of Creutzfeldt-Jakob disease

    Neurosci Lett

    (2002)
  • CollieDA et al.

    MRI of Creutzfeldt-Jakob disease: imaging features and recommended MRI protocol

    Clin Radiol

    (2001)
  • KanekoK et al.

    A synthetic peptide initiates Gerstmann-Sträussler-Scheinker (GSS) disease in transgenic mice

    JMol Biol

    (2000)
  • CollinsS et al.

    Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, and kuru: a review of these less common human transmissible spongiform encephalopathies

    JClinNeurosci

    (2001)
  • HillAF et al.

    Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples

    Lancet

    (1999)
  • WadsworthJD et al.

    Tissue distribution of protease resistant prion protein in variant Creutzfeldt-Jakob disease using a highly sensitive immunoblotting assay

    Lancet

    (2001)
  • HadlowWJ

    Scrapie and kuru

    Lancet

    (1959)
  • PrusinerSB

    Shattuck lecture: neurodegenerative diseases and prions

    N Engl J Med

    (2001)
  • CollingeJ et al.

    Inherited prion disease with 144 base pair gene insertion: 2, clinical and pathological features

    Brain

    (1992)
  • HillAF et al.

    The same prion strain causes vCJD and BSE

    Nature

    (1997)
  • BoltonDC et al.

    Identification of a protein that purifies with the scrapie prion

    Science

    (1982)
  • WalshDM et al.

    Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo

    Nature

    (2002)
  • KnausKJ et al.

    Crystal structure of the human prion protein reveals a mechanism for oligomerization

    Nat Struct Biol

    (2001)
  • Lopez GarciaF et al.

    NMR structure of the bovine prion protein

    Proc Natl Acad Sci USA

    (2000)
  • BrownDR et al.

    The cellular prion protein binds copper in vivo

    Nature

    (1997)
  • CollingeJ et al.

    Prion protein is necessary for normal synaptic function

    Nature

    (1994)
  • BurnsCS et al.

    Molecular features of the copper binding sites in the octarepeat domain of the prion protein

    Biochemistry

    (2002)
  • JoblingMF et al.

    Copper and zinc binding modulates the aggregation and neurotoxic properties of the prion peptide PrP106-126

    Biochemistry

    (2001)
  • JacksonGS et al.

    Location and properties of metal-binding sites on the human prion protein

    Proc Natl Acad Sci USA

    (2001)
  • BurnsCS et al.

    Copper coordination in the full-length, recombinant prion protein

    Biochemistry

    (2003)
  • PetersPJ et al.

    Trafficking of prion proteins through a caveolae-mediated endosomal pathway

    J Cell Biol

    (2003)
  • HarrisDA

    Clathrin-coated vesicles and detergent-resistant rafts in prion biology

    Bull Inst Pasteur

    (1998)
  • ShyngSL et al.

    A glycolipid-anchored prion protein is endocytosed via clathrin-coated pits

    J Cell Biol

    (1994)
  • CaugheyB et al.

    N-terminal truncation of the scrapie-associated form of PrP by lysosomal protease(s): implications regarding the site of conversion of PrP to the protease-resistant state

    J Virol

    (1991)
  • BaronGS et al.

    Conversion of raft associated prion protein to the protease-resistant state requires insertion of PrP-res (PrP(Sc)) into contiguous membranes

    Embo J

    (2002)
  • YedidiaY et al.

    Proteasomes and ubiquitin are involved in the turnover of the wild-type prion protein

    EMBO J

    (2001)
  • MaJ et al.

    Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol

    Science

    (2002)
  • MaJ et al.

    Conversion of PrP to a self-perpetuating PrPSc-like conformation in the cytosol

    Science

    (2002)
  • KociskoDA et al.

    Cell-free formation of protease-resistant prion protein

    Nature

    (1994)
  • JacksonGS et al.

    Reversible conversion of monomeric human prion protein between native and fibrilogenic conformations

    Science

    (1999)
  • ParamithiotisE et al.

    A prion protein epitope selective for the pathologically misfolded conformation

    Nat Med

    (2003)
  • LeclercE et al.

    Immobilized prion protein undergoes spontaneous rearrangement to a conformation having features in common with the infectious form

    EMBO J

    (2001)
  • KanekoK et al.

    Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation

    Proc Natl Acad Sci USA

    (1997)
  • PanKM et al.

    Conversion of -helices into -sheets features in the formation of the scrapie prion proteins

    ProcNatl Acad Sci USA

    (1993)
  • MeyerRK et al.

    Separation and properties of cellular and scrapie prion proteins

    Proc Natl Acad Sci USA

    (1986)
  • PriolaSA et al.

    Efficient conversion of normal prion protein (PrP) by abnormal hamster PrP is determined by homology at amino acid residue 155

    J Virol

    (2001)
  • ParchiP et al.

    Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease

    AnnNeurol

    (1996)
  • CollingeJ et al.

    Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD

    Nature

    (1996)
  • WadsworthJD et al.

    Strain-specific prion-protein conformation determined by metal ions

    Nat Cell Biol

    (1999)
  • HillAF et al.

    Protease-resistant prion protein produced in vitro lacks detectable infectivity

    J Gen Virol

    (1999)
  • Cited by (0)

    View full text