Neuropathogenesis of Prion Disease

Authors and Disclosures

Louise Davidson¹ & Richard Knight*¹

¹National Creutzfeldt–Jakob Disease Research & Surveillance Unit, University of Edinburgh, Edinburgh, UK.

*Author for correspondence r.knight@ed.ac.uk

Sidebar

Executive Summary

Background

• Prion diseases involve a post-translational misfolding of prion protein (PrP).

• Different forms of, and designations for, abnormal disease-related PrP exist.

Neuropathogenesis

• Three broad neuropathogenic mechanisms are proposed: loss of normal PrP function, abnormal PrP toxicity and a harmful interaction between normal and abnormal PrP.

Neuropathogenesis: depletion of PrP ^C

• Various normal of functions PrP ^C are proposed but not fully characterized.

• PrP ^C is subject to cellular processing, potentially relevant to neuropathogenesis.

• PrP-null mice models have aided exploration of this possible pathogenic mechanism.

• In general, there has been a trend away from loss of PrP ^C function explanations.

Neuropathogenesis: direct toxicity of abnormal PrP

• PrP ^Sc plays a crucial pathogenic role but is not necessarily directly neurotoxic.

• If abnormal PrP is neurotoxic, the relevant molecular species remains uncertain.

• Association of PrP ^Sc with toxicity:
  

  • Data indicate an uncertain and variable relationship between PrP ^Sc and neurotoxicity.

• Abnormal PrP in neurons or other cells:
  

  • It is important to consider PrP ^Sc toxicity in relation to its tissue location.

  • PrP ^Sc pathogenic toxicity may involve astrocytes and extracellular spaces.

• Possible toxic protein species:
  

  • Oligomeric intermediates between PrP ^C and PrP ^Sc may be the relevant toxic molecular species.

  • Certain parts of the physiological processing of PrP or minor 'aberrent' pathways of PrP ^C biosynthesis and processing could result in potentially toxic species.

  • There is, as of yet, no confirmed single or key toxic molecular species identified.

• Explorations of toxic protein species via genetic disease:
  

  • PRNP mutations have offered ways of studying potentially toxic protein species.

  • Studies based on genetic diseases have been interesting but inconclusive.

Neuropathogenesis: PrP ^C & PrP ^Sc interaction

• Interactions between normal PrP and some of its abnormal forms may be toxic; this has been termed a 'subversion of function'.

• If so, PrP ^C contributes to neurotoxicity in prion disease but by uncertain mechnisms.

Conclusion

• Loss of normal PrP ^C function does not appear to be the main pathogenic mechanism.

• Direct toxicity of abnormal PrP is possible, although mostly implicating oligomers intermediate between PrP ^C and PrP ^Sc or certain 'aberrant' or minor forms of PrP ^C.

• Potentially important interactions between PrP ^C and other proteins may be relevant for neurodegenerative diseases other than prion disease.