Prion protein (PrP) is not involved in the pathogenesis of spongiform encephalopathy in zitter rats (original) (raw)
Related papers
Prion disease induced alterations in gene expression in spleen and brain prior to clinical symptoms
Advances and Applications in Bioinformatics and Chemistry, 2008
Prion diseases are fatal neurodegenerative disorders that affect animals and humans. There is a need to gain understanding of prion disease pathogenesis and to develop diagnostic assays to detect prion diseases prior to the onset of clinical symptoms. The goal of this study was to identify genes that show altered expression early in the disease process in the spleen and brain of prion disease-infected mice. Using Affymetrix microarrays, we identifi ed 67 genes that showed increased expression in the brains of prion disease-infected mice prior to the onset of clinical symptoms. These genes function in many cellular processes including immunity, the endosome/lysosome system, hormone activity, and the cytoskeleton. We confi rmed a subset of these gene expression alterations using other methods and determined the time course in which these changes occur. We also identifi ed 14 genes showing altered expression prior to the onset of clinical symptoms in spleens of prion disease infected mice. Interestingly, four genes, Atp1b1, Gh, Anp32a, and Grn, were altered at the very early time of 46 days post-infection. These gene expression alterations provide insights into the molecular mechanisms underlying prion disease pathogenesis and may serve as surrogate markers for the early detection and diagnosis of prion disease.
Molecular medicine (Cambridge, Mass.), 2001
Some lines of mice homozygous for a disrupted prion protein gene (Prnp), including Ngsk Prnp(0/0) mice, exhibit Purkinje cell degeneration as a consequence of the ectopic overexpression of the downstream gene for prion protein-like protein (PrPLP/Dpl) in the brain, but others, such as Zrch I Prnp(0/0) mice, show neither the neurodegeneration nor the expression of PrPLP/Dpl. In the present study, we found that Ngsk Prnp(0/0), but not Zrch I Prnp(0/0) mice, developed gliosis involving both astrocytes and microglia in the brain. The brains from wild-type (Prnp(+/+)), Ngsk Prnp(0/0), Zrch I Prnp(0/0), and reconstituted Ngsk Prnp(0/0) mice carrying a mouse PrP transgene, designated Tg(P) Ngsk Prnp(0/0) mice, were subjected into Northern blotting and in situ hybridization using probes of glial fibrillary acidic protein (GFAP) and lysozyme M (LM) specific for astrocytes and microglia, respectively. Immunohistochemistry was also performed on the brain sections using anti-GFAP and anti-F4/80...
Prion Protein Signaling in the Nervous System—A Review and Perspective
Signal Transduction Insights, 2014
Prion protein (PrPC) was originally known as the causative agent of transmissible spongiform encephalopathy (TSE) but with recent research, its true function in cells is becoming clearer. It is known to act as a scaffolding protein, binding multiple ligands at the cell membrane and to be involved in signal transduction, passing information from the extracellular matrix (ECM) to the cytoplasm. Its role in the coordination of transmitters at the synapse, glyapse, and gap junction and in short- and long-range neurotrophic signaling gives PrPC a major part in neural transmission and nervous system signaling. It acts to regulate cellular function in multiple targets through its role as a controller of redox status and calcium ion flux. Given the importance of PrPC in cell physiology, this review considers its potential role in disease apart from TSE. The putative functions of PrPC point to involvement in neurodegenerative disease, neuropathic pain, chronic headache, and inflammatory dise...
Prion Protein Signaling in the Nervous System—A Review and Perspective
Signal Transduction Insights, 2014
Prion protein (PrP C ) was originally known as the causative agent of transmissible spongiform encephalopathy (TSE) but with recent research, its true function in cells is becoming clearer. It is known to act as a scaffolding protein, binding multiple ligands at the cell membrane and to be involved in signal transduction, passing information from the extracellular matrix (ECM) to the cytoplasm. Its role in the coordination of transmitters at the synapse, glyapse, and gap junction and in short-and long-range neurotrophic signaling gives PrP C a major part in neural transmission and nervous system signaling. It acts to regulate cellular function in multiple targets through its role as a controller of redox status and calcium ion flux. Given the importance of PrP C in cell physiology, this review considers its potential role in disease apart from TSE. The putative functions of PrP C point to involvement in neurodegenerative disease, neuropathic pain, chronic headache, and inflammatory disease including neuroinflammatory disease of the nervous system. Potential targets for the treatment of disease influenced by PrP C are discussed.
A Neurotoxic Prion Protein Fragment Induces Rat Astroglial Proliferation and Hypertrophy
European Journal of Neuroscience
Prion-related encephalopathies are characterized by the accumulation of an abnormal prion protein isoform (PrPsc) and the deposition of PrP amyloid in the brain. This process is accompanied by neuronal loss and astrogliosis. We recently showed that a synthetic peptide corresponding to residues 106-126 of human PrP is amyloidogenic and causes neuronal death by apoptosis in vitro. In the present study we investigated the effects of 1-and 1Cday exposures of rat astroglial cultures to micromolar concentrations of this peptide as well as peptides homologous to other portions of PrP, a peptide corresponding to residues 25-35 of amyloid-fl protein, and a scrambled sequence of PrP 106-126. No significant changes were observed after l-day exposure of cultures to any peptide. Conversely, 16day treatment with PrP 106-126 (50 pM) resulted in a 5-fold increase in glial fibrillary acidic protein (GFAP) expression, as evaluated by Northern and Western blot analyses, and a 1.5-fold increment in cell number. Light and electron microscopy immunohistochemistry showed an enlargement in size and density of astroglial processes, and an increase in GFAP-immunoreactive intermediate filaments. These changes were not observed after 1Cday treatment of cultures with the other peptides, including PrP 106-126 scrambled. The increase in GFAP expression of astroglial cultures exposed to PrP 106-126 was quantitatively similar to that found in scrapie-infected hamster brains. These results suggest that the PrP region corresponding to residues 106-126 is biologically active, and that cerebral accumulation of peptides including this sequence might be responsible for both the neuronal degeneration and the astrogliosis that occur in prion-related encephalopathies.
Experimental Neurology, 2009
Prion protein (PrP) is a host-encoded membrane-anchored glycoprotein which is required for susceptibility to prion disease. PrP may also be important for normal brain functions such as hippocampal spatial memory. Previously transgenic mice expressing amino terminally truncated mouse PrP (Δ32-134) spontaneously developed a fatal disease associated with degeneration of cerebellar granular neurons as well as vacuolar degeneration of deep cerebellar and brain stem white matter. This disease could be prevented by co-expression of wild-type (WT) mouse PrP on neurons or oligodendroglia. In the present experiments we studied Δ32-134 PrP transgenic mice with WT PrP expression restricted to astroglia, an abundant CNS cell-type important for neuronal viability. Expression of WT PrP in astroglia was sufficient to rescue 50% of mice from disease and prolonged survival by 200 days in the other 50%. We also found that transgenic mice expressing full-length soluble anchorless PrP had increased survival by 100 days. Together these two results indicated that rescue from neurodegeneration induced by Δ32-134 PrP might involve interactions between neurons expressing truncated PrP and nearby astrocytes expressing WT PrP or extracellular fluid containing soluble WT PrP.
A marked disparity between the expression of prion protein and its message by neurones of the CNS
Neuroscience, 2002
Expression of the normal cellular form of prion protein is both necessary and rate-limiting in the spread of prion disease, yet its cellular expression in vivo is poorly understood. To optimise immunohistochemical labelling of this protein in mouse brain, we have developed novel antibodies that recognise cellular prion protein in glutaraldehyde-fixed tissue. Expression was found to be predominantly neuronal, and to differ between different classes of neurone. Thus, neurones immunoreactive for GABA expressed very high levels of normal prion protein; most projection neurones expressed much lower levels, particularly on their axons in the major fibre tracts, and some neurones (e.g. those positive for dopamine) displayed no detectable prion protein. In marked contrast, all neurones, even those that were immunonegative, expressed high levels of message for prion protein, shown by non-radioactive in situ hybridisation. Glia expressed very low levels of message, and undetectable levels of ...
Neuron, 2007
Currently, no treatment can prevent the cognitive and motor decline associated with widespread neurodegeneration in prion disease. However, we previously showed that targeting endogenous neuronal prion protein (PrP C ) (the precursor of its disease-associated isoform, PrP Sc ) in mice with early prion infection reversed spongiform change and prevented clinical symptoms and neuronal loss. We now show that cognitive and behavioral deficits and impaired neurophysiological function accompany early hippocampal spongiform pathology. Remarkably, these behavioral and synaptic impairments recover when neuronal PrP C is depleted, in parallel with reversal of spongiosis. Thus, early functional impairments precede neuronal loss in prion disease and can be rescued. Further, they occur before extensive PrP Sc deposits accumulate and recover rapidly after PrP C depletion, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrP Sc . These data suggest that early intervention in human prion disease may lead to recovery of cognitive and behavioral symptoms.
PLoS ONE, 2014
Prion diseases induce neurodegeneration in specific brain areas for undetermined reasons. A thorough understanding of the localization of the disease-causing molecule, the prion protein (PrP), could inform on this issue but previous studies have generated conflicting conclusions. One of the more intriguing disagreements is whether PrP is synthesized by astrocytes. We developed a knock-in reporter mouse line in which the coding sequence of the PrP expressing gene (Prnp), was replaced with that for green fluorescent protein (GFP). Native GFP fluorescence intensity varied between and within brain regions. GFP was present in astrocytes but did not increase during reactive gliosis induced by scrapie prion infection. Therefore, reactive gliosis associated with prion diseases does not cause an acceleration of local PrP production. In addition to aiding in Prnp gene activity studies, this reporter mouse line will likely prove useful for analysis of chimeric animals produced by stem cell and tissue transplantation experiments.