Scrapie-associated PrP accumulation and agent replication: effects of sulphated glycosaminoglycan analogues

1994 ◽  
Vol 343 (1306) ◽  
pp. 399-404 ◽  
Keyword(s):  
Congo Red ◽  
Therapeutic Agents ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Scrapie Agent ◽  
Sulphated Glycosaminoglycans ◽  
Relative Potencies ◽  
Sulphated Glycosaminoglycan ◽  
Agent Replication

An abnormally protease-resistant and apparently neuropathogenic form of PrP accumulates in the brains of hosts with scrapie and related transmissible spongiform encephalopathies. Studies with scrapieinfected neuroblastom a cells have highlighted dramatic differences in the metabolism of the normal (protease-sensitive) and scrapie-associated (protease-resistant) isoforms of PrP. Furthermore, this model has been useful in identifying inhibitors of protease-resistant PrP accumulation and scrapie agent replication which are valuable as potential therapeutic agents and as probes of the mechanism of protease-resistant PrP formation. These inhibitors include the amyloid stain Congo red and certain sulphated glycans which are glycosaminoglycans themselves or glycosaminoglycan analogues. The relative potencies of various sulphated glycans correlate with their previously determ ined anti-scrapie activities in vivo , suggesting that the prophylactic effects of sulphated polyanions is due to inhibition of protease-resistant PrP accumulation. These and other observations suggest that an interaction of PrP with endogenous sulphated glycosaminoglycans or proteoglycans is important in protease-resistant PrP accumulation, and raise the possibility that therapies for transmissible spongiform encephalopathies and other amyloidoses could be based on blocking (pre)am yloid-glycosaminoglycan interactions.

scholarly journals Prion Disease Blood Test Using Immunoprecipitation and Improved Quaking-Induced Conversion

mBio ◽  
2011 ◽  
Vol 2 (3) ◽  
Author(s):  
Christina D. Orrú ◽  
Jason M. Wilham ◽  
Lynne D. Raymond ◽  
Franziska Kuhn ◽  
Björn Schroeder ◽  
...  
Keyword(s):  
Real Time ◽  
Blood Test ◽  
Prion Diseases ◽  
Proteinase K ◽  
Transmissible Spongiform Encephalopathies ◽  
Serum Samples ◽  
Spongiform Encephalopathies ◽  
Jakob Disease

ABSTRACT A key challenge in managing transmissible spongiform encephalopathies (TSEs) or prion diseases in medicine, agriculture, and wildlife biology is the development of practical tests for prions that are at or below infectious levels. Of particular interest are tests capable of detecting prions in blood components such as plasma, but blood typically has extremely low prion concentrations and contains inhibitors of the most sensitive prion tests. One of the latter tests is quaking-induced conversion (QuIC), which can be as sensitive as in vivo bioassays, but much more rapid, higher throughput, and less expensive. Now we have integrated antibody 15B3-based immunoprecipitation with QuIC reactions to increase sensitivity and isolate prions from inhibitors such as those in plasma samples. Coupling of immunoprecipitation and an improved real-time QuIC reaction dramatically enhanced detection of variant Creutzfeldt-Jakob disease (vCJD) brain tissue diluted into human plasma. Dilutions of 1014-fold, containing ~2 attogram (ag) per ml of proteinase K-resistant prion protein, were readily detected, indicating ~10,000-fold greater sensitivity for vCJD brain than has previously been reported. We also discriminated between plasma and serum samples from scrapie-infected and uninfected hamsters, even in early preclinical stages. This combined assay, which we call “enhanced QuIC” (eQuIC), markedly improves prospects for routine detection of low levels of prions in tissues, fluids, or environmental samples. IMPORTANCE Transmissible spongiform encephalopathies (TSEs) are largely untreatable and are difficult to diagnose definitively prior to irreversible clinical decline or death. The transmissibility of TSEs within and between species highlights the need for practical tests for even the smallest amounts of infectivity. A few sufficiently sensitive in vitro methods have been reported, but most have major limitations that would preclude their use in routine diagnostic or screening applications. Our new assay improves the outlook for such critical applications. We focused initially on blood plasma because a practical blood test for prions would be especially valuable for TSE diagnostics and risk reduction. Variant Creutzfeldt-Jakob disease (vCJD) in particular has been transmitted between humans via blood transfusions. Enhanced real-time quaking-induced conversion (eRTQ) provides by far the most sensitive detection of vCJD to date. The 15B3 antibody binds prions of multiple species, suggesting that our assay may be useful for clinical and fundamental studies of a variety of TSEs of humans and animals.

scholarly journals Creutzfeldt-Jakob’s disease: case report with emphasis on the electroencephalographic features

2005 ◽  
Vol 11 (4) ◽  
pp. 189-192
Author(s):  
Coral Patrícia ◽  
Francisco M. B. Germiniani ◽  
Carlos E. Silvado
Keyword(s):  
Neurodegenerative Disorder ◽  
Brain Mri ◽  
Infectious Complications ◽  
Transmissible Spongiform Encephalopathies ◽  
Progressive Dementia ◽  
Spongiform Encephalopathies ◽  
Disease Case ◽  
One Year ◽  
In Vivo Diagnosis

Creuzfeldt-Jakob’s Disease is a rare neurodegenerative disorder that is included among the transmissible spongiform encephalopathies. The clinical features are those of a rapid progressive dementia with mioclonic jerks, which progresses to death in less than one year. We report the case of a 79 years old woman, with initial complaints of vertigo, visual and gait compromise, with an initial brain MRI, EEG and CSF that had no specific features of CJD. After 12 days she was again admitted to the hospital with a worsening of her symptoms, along with global spasticity, inability to walk and a further deterioration of speech and swallowing. A new EEG disclosed periodic triphasic complexes, typical of the disease. CSF had a positive 14-3-3 protein. She later evolved with mioclonic jerks, coma, multiple infectious complications and, ultimately, death 45 days after her second admission. We focus on the role of the EEG as an adjuctive eletrophysiological tool for the presumptive in vivo diagnosis of the disease.

scholarly journals Gene-Based Antibody Strategies for Prion Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Alessio Cardinale ◽  
Silvia Biocca
Keyword(s):  
Therapeutic Potential ◽  
Prion Diseases ◽  
Recombinant Antibody ◽  
Cellular Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Diagnostic Tools ◽  
Spongiform Encephalopathies ◽  
Interaction Sites

Prion diseases or transmissible spongiform encephalopathies (TSE) are a group of neurodegenerative and infectious disorders characterized by the conversion of a normal cellular protein PrPCinto a pathological abnormally folded form, termed PrPSc. There are neither available therapies nor diagnostic tools for an early identification of individuals affected by these diseases. New gene-based antibody strategies are emerging as valuable therapeutic tools. Among these, intrabodies are chimeric molecules composed by recombinant antibody fragments fused to intracellular trafficking sequences, aimed at inhibiting,in vivo, the function of specific therapeutic targets. The advantage of intrabodies is that they can be selected against a precise epitope of target proteins, including protein-protein interaction sites and cytotoxic conformers (i.e., oligomeric and fibrillar assemblies). Herein, we address and discussin vitroandin vivoapplications of intrabodies in prion diseases, focussing on their therapeutic potential.

scholarly journals Sulphated glycosaminoglycans prevent the neurotoxicity of a human prion protein fragment

1998 ◽  
Vol 335 (2) ◽  
pp. 369-374 ◽  
Author(s):  
Mar PÉREZ ◽  
Francisco WANDOSELL ◽  
Camilo COLAÇO ◽  
Jesús AVILA
Keyword(s):  
Prion Protein ◽  
Amyloid Fibrils ◽  
Transmissible Spongiform Encephalopathies ◽  
Therapeutic Effects ◽  
Protein Fragment ◽  
Spongiform Encephalopathies ◽  
Sulphated Polysaccharides ◽  
Human Prion Protein ◽  
Sulphated Glycosaminoglycans

Although a number of features distinguish the disease isoform of the prion protein (PrPSc) from its normal cellular counterpart (PrPC) in the transmissible spongiform encephalopathies (TSEs), the neuropathogenesis of these diseases remains an enigma. The amyloid fibrils formed by fragments of human PrP have, however, been shown to be directly neurotoxic in vitro. We show here that sulphated polysaccharides (heparin, keratan and chondroitin) inhibit the neurotoxicity of these amyloid fibrils and this appears to be mediated via inhibition of the polymerization of the PrP peptide into fibrils. This provides a rationale for the therapeutic effects of sulphated polysaccharides and suggests a rapid in vitro functional screen for TSE therapeutics.

scholarly journals Congo red inhibition of scrapie agent replication.

1993 ◽  
Vol 67 (10) ◽  
pp. 6270-6272 ◽  
Author(s):  
B Caughey ◽  
D Ernst ◽  
R E Race
Keyword(s):  
Congo Red ◽  
Scrapie Agent ◽  
Agent Replication

scholarly journals Neuroprotective role of PrPC against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7–PSD-95 binding

2011 ◽  
Vol 22 (17) ◽  
pp. 3041-3054 ◽  
Author(s):  
Patricia Carulla ◽  
Ana Bribián ◽  
Alejandra Rangel ◽  
Rosalina Gavín ◽  
Isidro Ferrer ◽  
...  
Keyword(s):  
Prion Protein ◽  
Knockout Mice ◽  
Neuronal Excitability ◽  
Epileptic Seizures ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Glycosyl Phosphatidylinositol

Cellular prion protein (PrPC) is a glycosyl-phosphatidylinositol–anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrPSC) induces transmissible spongiform encephalopathies. In contrast, PrPC has a number of physiological functions in several neural processes. Several lines of evidence implicate PrPC in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrPC has been implicated in the inhibition of N-methyl-d-aspartic acid (NMDA)–mediated neurotransmission, and prion protein gene (Prnp) knockout mice show enhanced neuronal death in response to NMDA and kainate (KA). In this study, we demonstrate that neurotoxicity induced by KA in Prnp knockout mice depends on the c-Jun N-terminal kinase 3 (JNK3) pathway since Prnpo/oJnk3o/o mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrPC-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrPC with postsynaptic density 95 protein (PSD-95) and glutamate receptor 6/7 (GluR6/7). Indeed, GluR6–PSD-95 interaction after KA injections was favored by the absence of PrPC. Finally, neurotoxicity in Prnp knockout mice was reversed by an AMPA/KA inhibitor (6,7-dinitroquinoxaline-2,3-dione) and the GluR6 antagonist NS-102. We conclude that the protection afforded by PrPC against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation.

scholarly journals Toxicological Evaluation of Anti-Scrapie Trimethoxychalcones and Oxadiazoles

2015 ◽  
Vol 87 (2 suppl) ◽  
pp. 1421-1434 ◽  
Author(s):  
CLAUDIA P. FIGUEIREDO ◽  
NATALIA C. FERREIRA ◽  
GISELLE F. PASSOS ◽  
ROBSON DA COSTA ◽  
FERNANDA S. NEVES ◽  
...  
Keyword(s):  
Prion Protein ◽  
Aromatic Compounds ◽  
Prion Diseases ◽  
Intraperitoneal Administration ◽  
Neuroblastoma Cells ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Toxicological Evaluation ◽  
Spongiform Encephalopathies

An altered form of the cellular prion protein, the PrPScor PrPRes, is implicated in the occurrence of the still untreatable transmissible spongiform encephalopathies. We have previously synthesized and characterized aromatic compounds that inhibit protease-resistant prion protein (PrPRes) accumulation in scrapie-infected cells. These compounds belong to different chemical classes, including acylhydrazones, chalcones and oxadiazoles. Some of the active compounds were non-toxic to neuroblastoma cells in culture and seem to possess drugable properties, since they are in agreement with the Lipinski´s rule of 5 and present desirable pharmacokinetic profiles as predicted in silico. Before the evaluation of the in vivo efficacy of the aromatic compounds in scrapie-infected mice, safety assessment in healthy mice is needed. Here we used Swiss mice to evaluate the acute toxicity profile of the six most promising anti-prionic compounds, the 2,4,5-trimethoxychalcones (J1, J8, J20 and J35) and the 1,3,4-oxadiazoles (Y13 and Y17). One single oral administration (300 mg/kg) of J1, J8, J20, J35, Y13 and Y17 or repeated intraperitoneal administration (10 mg/kg, 3 times a week, for 4 weeks) of J1, J8 and J35, did not elicit toxicity in mice. We strongly believe that the investigated trimethoxychalcones and oxadiazoles are interesting compounds to be further analyzed in vivo against prion diseases.

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