Mechanisms of Cell Death in the Transmissible Spongiform Encephalopathies

The transmissible spongiform encephalopathies (TSEs) constitute a family of fatal, neurodegenerative diseases, including scrapie in sheep, chronic wasting disease (CWD) in deer and elk, bovine spongiform encephalopathy (BSE) and a range of human disorders, such as Creutzfeldt-Jakob disease (CJD), kuru and fatal familial insomnia. The archetypal TSE disease is scrapie of sheep and goats, which has been present in the UK flock for over 200 years as a result of both horizontal and vertical transmission. The most prevalent TSE disease of humans is sporadic Creutzfeldt-Jakob disease (spCJD), which affects 1-3 individuals per million worldwide. A new form of CJD, known as variant CJD (vCJD), was diagnosed in humans in the mid 1990s and it is likely that vCJD was contracted by consumption of contaminated beef, since this disease is indistinguishable from BSE on transmission to a panel of mice (Bruce et al., 1997). To date, there have been 175 cases of vCJD in the UK and a further 49 cases across 11 other countries (www.eurocjd.ed.ac.uk, data correct as of Aug 2011).


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The transmissible spongiform encephalopathies (TSEs) constitute a family of fatal,  fibrils. The prion protein is ubiquitously expressed, but is most abundant in the central 26 nervous system (CNS). Hence accumulation of PrP Sc occurs principally in the brain, but 27 peripheral lymphoreticular tissues can also accumulate proteinaceous deposits. The prion 28 hypothesis suggests that PrP Sc is the infectious agent in TSE diseases and that it catalytically 29 causes nascent PrP C molecules also to misfold (Prusiner, 1998). TSEs exist as discrete strains 30 of disease, which can be stably passaged in suitable hosts resulting in differences in       24 dysfunction also appears to be a consistent, early pathological sign in many other 25 neurodegenerative diseases, but there are suggestions that the exact morphological changes 26 seen may differ depending on whether the insults to synapses are caused by processes leading to intra-or extra-cellular protein deposits. In addition, synaptic dysfunction in prion 1 diseases differs from that seen during Wallerian degeneration in the periphery, in which 2 axons are dissected or otherwise compromised and presynapses retract (Gillingwater et al., 3 2003). In prion diseases, loss of synapses appears to be followed by a retraction of the 4 dendritic spine, but whether loss of any given synapse impacts on neighbouring synapses 5 and ultimately on the respective cell body remains to be determined.

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The early loss of synapses in prion disease must occur in response to a disease-associated 7 molecular event or biochemical pathway. It is possible that this event may be the beginnings 8 of the misfolded protein cascade, since in C57BL/6 mice infected with ME7 scrapie the 9 accumulation of PrP Sc can be detected at week 8, before the first observable signs of synaptic 10 defects. The first deposits of abnormal PrP accumulate in the dentate gyrus of the 11 hippocampus, subsequently spreading to encompass the CA3 sub-region of the 12 hippocampus (Gray, et al., 2009). This suggests a progression of PrP Sc formation along the        There are also suggestions that microglia are not involved in the neurodegenerative process 8 at all, but that degeneration is a neuron-autonomous process, at least at early stages (Perry &

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Contradictory evidence comes from studies in PrP C -null mice transgenically expressing 30 hamster PrP C exclusively on astrocytes; these mice were capable of supporting hamster-31 passaged prion disease and developed clinical signs, indicating that neuronal PrP C was not 32 necessary for neuronal degeneration (Raeber et al., 1997). In the same studies, astrocytic 33 hamster PrP C was expressed in mice in addition to wild type murine PrP C and these mice    4 The globular C-terminal region incorporates two consensus sites for N-linked glycosylation, 5 a single disulphide bond and a glycosylphosphatidyl inositol (GPI) membrane anchor is 6 appended to the extreme C-terminus. After conversion of PrP C to PrP Sc , the C-terminal 7 domain is resistant to protease digestion, indicating that it is this section of the protein that 8 undergoes conformational change during prion protein misfolding.

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By contrast to PrP C , atomic level detail of PrP Sc tertiary structure is lacking, which is a result     PrP C that had been highly purified from brain tissue to which polyanionic species (RNA or 4 glycosaminoglycans) were added. This mixture was sufficient to allow amplification of 5 abnormal PrP when seeded with PrP Sc , but also allowed the generation of abnormal PrP de 6 novo in the absence of a catalytic seed. Crucially, the newly-synthesised abnormal PrP was 7 shown to cause a TSE-like disease after inoculation to wild type animals. These data imply 8 that purified PrP C (along with lipids that co-purified with the protein) in addition to a

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In summary, although we know the structure of PrP C to atomic resolution and we can