Acta Neuropathol (Berl). 2002 Sep;104(3):320-6. Epub 2002 May 08. Distribution of intraneuronal immunoreactivity for the prion protein in human prion diseases.
Kovacs GG, Voigtlander T, Hainfellner JA, Budka H.
Institute of Neurology, University of Vienna, AKH 4J, Wahringer Gurtel 18-20, POB 48, 1097 Vienna, Austria.
Intraneuronal prion protein (PrP) immunoreactivity (INIR), which might represent the non-pathological, cellular form of PrP, needs to be distinguished from disease-associated deposits specific for prion disease (PrD). In adjacent sections of PrD and control brains we applied pretreatments, one of which enhances the immunoreactivity of disease-associated PrP, and another that enhances INIR. We observed an inverse correlation between the proportion of neurons with INIR and the intensity of disease-associated PrP immunoreactivity and severity of lesions. Additionally, we found large intracytoplasmic inclusion-like bodies in ballooned neurons in PrD cases. We noted that the 3F4 (epitope: amino acids 109-112) anti-PrP antibody labels more INIR than antibodies directed against amino acids 23-85 (BG4) or 140-180 (KG9) in PrD cases, in contrast to controls, but all antibodies immunolabel more INIR in PrD brains. The up-regulation of PrP might represent an early loss of function of the non-pathological form of PrP, in parallel with a neurotoxic effect of accumulating disease-associated isoform, as part of the pathogenesis of prion diseases.
PMID:_12172919
Neuropathol Appl Neurobiol. 2002 Aug;28(4):314-24. Brain biopsy in Creutzfeldt-Jakob disease: evolution of pathological changes by prion protein immunohistochemistry.
Mahadevan A, Shankar SK, Yasha TC, Santosh V, Sarkar C, Desai AP, Satishchandra P.
Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India.
The formation of protease-resistant prion protein (PrPsc) is considered to be an early event in the pathogenesis of Creutzfeldt-Jakob disease (CJD) and hence its demonstration in brain biopsies by immunohistochemistry is considered diagnostic. We analysed eight brain biopsies from the frontal cortex collected from different parts of India from cases diagnosed as CJD on clinical and pathological grounds for the expression of prion protein (PrP). The duration of illness in these cases varied from 2 months to 1 year. Immunohistochemistry was carried out on paraffin sections using two different clones (KG9 and 3F4) of monoclonal antibodies to PrP. Although all eight cases showed classical features of spongiform encephalopathy of varying severity, only five of the eight cases revealed PrP(sc) in the brain tissue. The immunolabelling was focal and all areas with spongiform change were not labelled. A temporal evolution in the staining pattern was evident - particulate diffuse labelling (synaptic type) in early stages (2 months), perivacuolar deposits in intermediate stages (5-6 months), and dense plaques in late stages (12 months).
PMID:_12175344
Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16384-91. Epub 2002 Aug 12. Conservation of a portion of the S. cerevisiae Ure2p prion domain that interacts with the full-length protein.
Edskes HK, Wickner RB.
Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0830, USA.
The [URE3] prion of Saccharomyces cerevisiae is a self-propagating inactive amyloid form of the Ure2 protein. Ure2p residues 1-65 constitute the prion domain, and the remaining C-terminal portion regulates nitrogen catabolism. We have examined the URE2 genes of wild-type isolates of S. cerevisiae and those of several pathogenic yeasts and a filamentous fungus. We find that the normal function of the S. cerevisiae Ure2p in nitrogen regulation is fully complemented by the Ure2p of Candida albicans, Candida glabrata, Candida kefyr, Candida maltosa, Saccharomyces bayanus, and Saccharomyces paradoxus, all of which have high homology in the C-terminal nitrogen regulation domain. However, there is considerable divergence of their N-terminal domains from that of Ure2p of S. cerevisiae. [URE3(Sc)] showed efficient transmission into S. cerevisiae ure2Delta cells if expressing a Ure2p of species within Saccharomyces. However, [URE3(Sc)] did not seed self-propagating inactivation of the Ure2p's from the other yeasts. When overexpressed as a fusion with green fluorescent protein, residues 5-47 of the S. cerevisiae prion domain are necessary for curing the [URE3] prion. Residues 11-39 are necessary for an inactivating interaction with the full-length Ure2p. A nearly identical region is highly conserved among many of the yeasts examined in this study, despite the wide divergence of sequences found in other parts of the N-terminal domains.
PMID:_12177423
Neurosci Lett. 2002 Sep 6;329(3):269-72. The prion protein in human neurodegenerative disorders.
Kovacs GG, Zerbi P, Voigtlander T, Strohschneider M, Trabattoni G, Hainfellner JA, Budka H.
Institute of Neurology, University of Vienna, and Austrian Reference Centre for Human Prion Diseases, AKH 4J, Wahringer Gurtel 18-20, PO Box 48, A-1097 Vienna, Austria.
We evaluate cellular prion protein (PrP(C)) immunoreactivity (IR) in Alzheimer's, Parkinson's, diffuse Lewy body, and motor neuron diseases (MND), progressive supranuclear palsy, and multiple system atrophy. We use immunohistochemistry for PrP, including five monoclonal antibodies against different epitopes and three different pretreatments, alpha-synuclein, phosphorylated tau, beta-amyloid, and ubiquitin. Disease-specific inclusions are devoid of PrP(C) IR. Using double immunofluorescence and confocal laser microscopy we observe focal overlapping of PrP(C) with tau and with alpha-synuclein in early, but not in fully developed inclusions. However, PrP(C) IR neurons may contain abnormal tau or alpha-synuclein aggregates. Additionally, we observe a loss of PrP(C) IR in anterior horn neurons in MND. Our results suggest that expression of PrP(C) reflects a general response to cellular stress rather than specific co-operation in aggregation of other proteins.
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