Intraneuronal immunoreactivity for the prion protein distinguishes a subset of E200K genetic from sporadic Creutzfeldt-Jakob Disease.
Recently, we reported widespread intraneuronal prion protein (PrP) immunoreactivity in genetic Creutzfeldt-Jakob disease (CJD) associated with the E200K mutation. Here, we evaluated 6 cases ofsporadic CJD MM type 1, 5 MV type 2, and 7 VV type 2 and compared their anatomical appearance with that of 29 E200K genetic CJD (gCJD) cases. We also performed double immunolabeling for ubiquitin, p62, early endosomal marker rab5, and immunogold electronmicroscopy in 3 cases. We identified 4 morphological types of intraneuronal PrP immunoreactivity: one type, defined as multiple globular structures, was significantly associated with a subset of E200K gCJD cases and was distinct from the intraneuronal small dotlike PrP immunoreactivity seen in sporadic CJD. Whereas the latter colocalized with rab5, there were single large (7.5 μm-15 μm) globular inclusion body-like structures detected predominantly but not exclusively in E200K gCJD; these were immunoreactive in part for ubiquitin and p62 and showed focal γ-tubulin immunoreactivity, suggesting aggresome features. Ultrastructural examination using immunogold revealed PrP localization in aggresome-like structures and in autophagic vacuoles. These findings suggest that the permanent production of mutant PrP in the E200K gCJD cases overwhelms the ubiquitin-proteasome system and shifts the balance toward selectivemacroautophagy and/or to ubiquitinated inclusion body and aggresome formation as a cytoprotective effort to sequester the mutant protein.
Institute of Neurology, and Austrian Reference Center for Human Prion Diseases, Medical University of Vienna, Vienna, Austria.
Gabor G
GG
Kovacs
Kinga
K
Molnár
Eva
E
Keller
Gergő
G
Botond
Herbert
H
Budka
Lajos
L
László
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000368:Aged; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016009:Chi-Square Distribution; D007562:Creutzfeldt-Jakob Syndrome / Q000145:classification / Q000235:genetics / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000235:genetics*; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism* / Q000648:ultrastructure; D008239:Lysine / Q000235:genetics*; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology* / Q000648:ultrastructure; D011328:Prions / Q000145:classification / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D051843:Synucleins / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D011328:Prions; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D051843:Synucleins; D014404:Tubulin; D018698:Glutamic Acid; D020696:rab5 GTP-Binding Proteins; D008239:Lysine