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Subcellular and Molecular Changes Associated with Abnormal PrP Accumulation in Brain and Viscera of Classical and Atypical Prion Diseases

  • Martin JeffreyEmail author
  • Gillian McGovern
Protocol
  • 365 Downloads
Part of the Neuromethods book series (NM, volume 129)

Abstract

Immunogold electron microscopy has shown that the primary toxic effects on cells of disease-associated prion protein (PrPd) accumulation are to be found on plasma membranes. The nature of the membrane change is tissue and cell type specific. PrPd accumulation on neurites is associated with bizarre and unique twisted or branched membrane invaginations that are sometimes coated and sometimes have a spiral twist. Neuronal PrPd elicits submembrane ubiquitination by interaction with a presumptive transmembrane ligand and this protein complex undergoes clathrin-mediated endocytosis. PrPd accumulation on plasma membranes of glial cells causes membrane ruffling but on follicular dendritic cells of the lymphoid system it causes dendritic process hyperplasia, while on adrenal chromaffin cells it causes the membrane to be rearranged into linear palisades. PrPd interacts with different molecular partners on different cells suggesting that these different morphological defects are caused by variable molecular interactions related to a scaffolding function of normal membrane PrP. The presence of a glycophosphoinositol (GPI) anchor is necessary for membrane binding and pathology. The absence of a GPI anchor promotes release of PrPd into interstitial fluid and, on interaction with extracellular matrix binding proteins, its accumulation in basement membranes of blood vessels to form cerebral amyloid angiopathy. Membrane PrPd may be released to the extracellular space to form amyloid fibrils or be internalized into the endolysosomal systems where it is initially N-terminally truncated prior to complete degradation. These three subcellular locations of PrPd, plasma membranes, endolysosomes, and extracellular aggregates of PrPd, are common to all classical prion diseases and prion disease sources in man, sheep, cattle, and deer. However, atypical scrapie PrPd may be found on membranes of myelinated axons and in the inner mesaxon of oligodendroglial cells suggesting that differing trafficking pathways for PrPd occur in atypical scrapie relative to classical prion diseases. While PrPd is consistently associated with cellular lesions that most likely contribute to neurological deficits, it is unlikely that PrPd colocalized lesions are, alone, the proximate cause of clinical disease. Other lesions such as apoptosis that do not colocalize with PrPd may contribute to clinical disease progression and may be associated indirectly with increasing PrPd accumulation. However, prion disease-infected tissues possess other lesions, such as tubulovesicular bodies, that do not have clear association with PrPd and are of unknown relationship to disease pathogenesis.

Key words

Transmissible spongiform encephalopathy Atypical scrapie Prion disease Immunogold electron microscopy Prion protein Cell membranes Tubulovesicular bodies Cerebral amyloid angiopathy Mesaxon Lymphoid tissues Adrenal Brain Follicular dendritic cell 

Notes

Acknowledgements

This work was financially supported by Defra. We are grateful to the many collaborators who have made this work possible and to Callum Donnelly for expert technical assistance.

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© Springer Science+Business Media LLC 2017

Authors and Affiliations

  1. 1.Animal and Plant Health Agency, Lasswade Veterinary LaboratoryPentlands Science ParkPenicuikUK

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