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

Abstract

Immunogold electron microscopy has shown that the primary toxic effects on cells of disease-associated prion protein (PrP^d) accumulation are to be found on plasma membranes. The nature of the membrane change is tissue and cell type specific. PrP^d 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 PrP^d elicits submembrane ubiquitination by interaction with a presumptive transmembrane ligand and this protein complex undergoes clathrin-mediated endocytosis. PrP^d 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. PrP^d 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 PrP^d 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 PrP^d 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 PrP^d, plasma membranes, endolysosomes, and extracellular aggregates of PrP^d, are common to all classical prion diseases and prion disease sources in man, sheep, cattle, and deer. However, atypical scrapie PrP^d may be found on membranes of myelinated axons and in the inner mesaxon of oligodendroglial cells suggesting that differing trafficking pathways for PrP^d occur in atypical scrapie relative to classical prion diseases. While PrP^d is consistently associated with cellular lesions that most likely contribute to neurological deficits, it is unlikely that PrP^d colocalized lesions are, alone, the proximate cause of clinical disease. Other lesions such as apoptosis that do not colocalize with PrP^d may contribute to clinical disease progression and may be associated indirectly with increasing PrP^d accumulation. However, prion disease-infected tissues possess other lesions, such as tubulovesicular bodies, that do not have clear association with PrP^d and are of unknown relationship to disease pathogenesis.