Chapter 57 : Transmissible Spongiform Encephalopathies

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Prion diseases, also termed transmissible spongiform encephalopathies (TSEs), are inevitably fatal neurodegenerative conditions which affect humans and a wide variety of animals. The most common form of prion disease in humans is sporadic Creutzfeldt-Jakob disease (sCJD). Human studies also point to a possible role for members of the classical complement cascade in prion pathogenesis; however, their precise role in prion disease is unknown. The majority of cases were caused by implantation of dura mater and injection of pituitary growth hormone. There is uncertainty surrounding the danger of transmission to humans represented by chronic wasting disease. In fact, even transmissibility of bovine spongiform encephalopathy (BSE) to humans relies on circumstantial evidence. Recent advances in neuroimaging, and especially in magnetic resonance imaging (MRI), have revealed that different human prion diseases have specific patterns. Tissue should be fixed in formalin for histologic assessment and snap-frozen for Western blotting. Western blotting of digested PrP reveals three distinct bands, corresponding to di-, mono-, and unglycosylated forms. Depending on the exact conditions under which the protease digestion and the Western blotting procedure are performed, between three and six different PrP types can be distinguished. The fact that the PrP types found in variant CJD (vCJD) patients and in BSE-diseased cattle are identical is one of the main arguments supporting the theory that BSE prions are responsible for the vCJD epidemic in humans.

Citation: Aguzzi A. 2009. Transmissible Spongiform Encephalopathies, p 1307-1324. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch57
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Image of FIGURE 1

Model for prion strain propagation and detection. PrP (cube) exists in equilibrium with a misfolded monomeric isoform (cross). The latter can assemble into structurally heterogeneous yet highly ordered aggregated forms (upper versus lower assemblies) which replicate differentially in select cell lines. A panel of such lines, as provided by Mahal and colleagues, may form the basis for classifying prions. When stained with luminescent conjugated thiophene polymers, PrP aggregates stemming from distinct prion strains fluoresce in different colors.

Citation: Aguzzi A. 2009. Transmissible Spongiform Encephalopathies, p 1307-1324. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch57
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Image of FIGURE 2

Models for the conformational conversion of PrP into PrP. (A) The “refolding” or template assistance model postulates an interaction between exogenously introduced PrP and endogenous PrP, which is induced to transform itself into further PrP. A high energy barrier may prevent spontaneous conversion of PrP into PrP. (B) The “seeding” or nucleation-polymerization model proposes that PrP and PrP are in a reversible thermodynamic equilibrium. Only if several monomeric PrP molecules are mounted into a highly ordered seed can further monomeric PrP be recruited and eventually aggregate to amyloid. Within such a crystal-like seed, PrP becomes stabilized. Fragmentation of PrP aggregates increases the number of nuclei, which can recruit further PrP and thus results in apparent replication of the agent.

Citation: Aguzzi A. 2009. Transmissible Spongiform Encephalopathies, p 1307-1324. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch57
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Image of FIGURE 3

Western blot analysis of PrP. The currently most popular classification schemes for CJD ( ) reliably discriminate PrP types based on the mobility of the unglycosylated band of PrP and the signal intensity of di-, mono-, and unglycosylated forms of PrP. One scheme ( ) differentiates four principal PrP types (1 to 4) ( ). Three principal PrP types (1, 2a, and 2b) are proposed in the second scheme ( ). MM, homozygous methionine; MV, heterozygous methionine valine; VV, homozygous valine.

Citation: Aguzzi A. 2009. Transmissible Spongiform Encephalopathies, p 1307-1324. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch57
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Generic image for table

Synopsis of currently used prion strain differentiation assays

Citation: Aguzzi A. 2009. Transmissible Spongiform Encephalopathies, p 1307-1324. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch57
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Response of the cell panel to four murine prion strains

Citation: Aguzzi A. 2009. Transmissible Spongiform Encephalopathies, p 1307-1324. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch57
Generic image for table

Human prion diseases: clinical features

Citation: Aguzzi A. 2009. Transmissible Spongiform Encephalopathies, p 1307-1324. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch57
Generic image for table

Useful supplemental diagnostic tests and specimens for CJD

Citation: Aguzzi A. 2009. Transmissible Spongiform Encephalopathies, p 1307-1324. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch57

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