Prion Protein with an Insertional Mutation Accumulates on Axonal and Dendritic Plasmalemma and Is Associated with Distinctive Ultrastructural Changes

Abstract

Prion diseases are fatal neurological diseases characterized by central nervous system deposition of abnormal forms of a membrane glycoprotein designated PrP (prion protein). Tg(PG14) transgenic mice express PrP that harbor a nine-octapeptide insertional mutation homologous to one described in a familial prion disease of humans. Tg(PG14) mice spontaneously develop a fatal neurological illness accompanied by massive apoptosis of cerebellar granule neurons and accumulation of an aggregated and weakly protease-resistant form of PrP that is not infectious. Previous light microscopic analyses of these mice left open questions regarding the subcellular distribution of the mutant protein and the nature of the neuropathological lesions produced. To address these questions, we undertook an immunogold electron microscopic study of Tg(PG14) mice. We found that mutant PrP is localized primarily on the plasma membrane of dendrites and unmyelinated axons in the hippocampus and cerebellum, with little labeling of either neuronal cell bodies or intracellular organelles. PrP deposits were shown to be associated with degenerative changes in dendritic structure. We also describe for the first time marked pathology in myelinated axons , and alterations in the axon/oligodendrocyte interface. Taken together , our results suggest cellular mechanisms by which mutant PrPs produce pathology. In addition, they highlight distinctions between familial and infectious prion disorders at the ultrastructural level that correlate with differences in cellular trafficking of the disease-

How structure shapes (dys)function

“…In Creutzfeldt-Jakob disease, the most common prion disease in humans, cerebellar alterations are well documented; 5 notably, flattening and reduction of dendritic arbors of Purkinje cells have been reported 6 . In agreement with the studies above, dendrite degeneration was described as a feature of cerebellar pathology in a mouse model of another human prion disease Gerstmann-Sträussler-Scheinker syndrome 7 . However, synaptic degeneration occurred in the cerebellum infected with a different prion strain (RML) in TG3 mice, a transgenic mouse line in which the prion protein was expressed exclusively in astrocytes 8 .…”

Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrPSc) deposition in sporadic Creutzfeldt–Jakob disease supports a pathogenic role for small PrPSc deposits common to the various molecular subtypes

“…By colocalization with synaptophysin and synapsin I, fine diffuse small PrP Sc deposits have been shown in presynaptic structures, in the brain of sCJD cases [28]. In contrast, the results of immunogold electron microscopic investigation of Tg( PG14 ) mice that develop a fatal neurological illness accompanied by massive apoptosis of CGN demonstrate that punctate PG14‐PrP accumulates on the plasma membranes of dendrites and axons with no association with pre‐ or post‐synaptic densities and is associated with degenerative changes in dendritic structure [29]. Several studies of infectious prion diseases have shown – in animal models – that PrP Sc accumulates primarily on plasma membranes, at the level of the neuronal cell body and dendrites [30–32] and causes severe synaptic dysfunction before nerve cell death, with dendritic degeneration occurring early in the course of the disease [31,33].…”

Altered trafficking of abnormal prion protein in atypical scrapie: prion protein accumulation in oligodendroglial inner mesaxons

“… showed mutations of the octapeptide repeat sequence. Tg(PG14) transgenic mice also express a nine‐octapeptide insertional mutation homologous to that of a familial prion disease of humans and these mice transport a weakly protease resistant form of prion protein in axons which accumulates in linear segments on neurite membranes in the region of synaptic terminals . Tg(PG14) mice also show abnormal proliferation of the inner oligodendroglial mesaxon and segmental demyelination although abnormal PrP d has not been specifically detected at these sites .…”