A5013457359- Prion Diseases and Protein Misfolding
- Neurological diseases and metabolism
- Trace Elements in Health
- Enzyme Structure and Function
- DNA and Nucleic Acid Chemistry
- RNA Interference and Gene Delivery
- Animal Genetics and Reproduction
- Alzheimer's disease research and treatments
- Venomous Animal Envenomation and Studies
- Infectious Encephalopathies and Encephalitis
- Neuroinflammation and Neurodegeneration Mechanisms
- Calpain Protease Function and Regulation
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Cancer therapeutics and mechanisms
- Connexins and lens biology
- HIV Research and Treatment
- RNA regulation and disease
Colorado State University
2015-2025
National Animal Disease Center
2023-2024
United States Department of Agriculture
2024
Agricultural Research Service
2024
Oak Ridge Institute for Science and Education
2024
Iowa State University
2024
Ames National Laboratory
2024
Oak Ridge Associated Universities
2024
Finnish Food Authority
2023
Norwegian Veterinary Institute
2023
Prions are infectious proteins causing fatal, transmissible neurodegenerative diseases of animals and humans. Replication involves template-directed refolding host encoded prion protein, PrP C , by its conformation, Sc . Following discovery in captive Colorado deer 1967, uncontrollable contagious transmission chronic wasting disease (CWD) led to an expanded geographic range increasing numbers free-ranging North American (NA) cervids. Some five decades later, detection Norwegian (NO) reindeer...
Our previous studies using gene-targeted mouse models of chronic wasting disease (CWD) demonstrated that Norway and North America cervids are infected with distinct prion strains respond differently to naturally occurring amino acid variation at residue 226 the protein. Here we performed transmissions in mice investigate properties prions causing newly emergent CWD moose Finland. Although from Finland had comparable responses primary structural differences 226, other distinctive criteria,...
Cell-based measurement of prion infectivity is currently restricted to experimental strains mouse-adapted scrapie. Having isolated cell cultures with susceptibility prions from diseased elk, we describe a modification the scrapie assay allowing evaluation causing chronic wasting disease, naturally occurring transmissible spongiform encephalopathy. We compare this cervid bioassays in transgenic mice, only other existing method for quantification, and show be relatively economical expedient...
Significance Searching for drugs to prevent conversion of host-encoded prion protein (PrP C ) its infectious conformation Sc is a key strategy in the pursuit therapies disorders: fatal, transmissible epidemic diseases unpredictable occurrence and uncertain zoonotic potential. Despite quinacrine’s ability reduce mouse PrP cell models, use treat patients has been unsuccessful. Here, we show that quinacrine augments intensifies replication prions, causing chronic wasting disease deer, elk,...
Significance To study mechanisms of interspecies prion transmission, we used transgenic mice that recapitulate natural disease susceptibilities. Predictably, prions from a particular species inefficiently caused in expressing proteins different species. However, contrast to the expected adaptation allows efficient replication new host, discovered process which pathogenic prions, despite causing on primary passage, failed adapt for sustained propagation instead preserving strain and host...
ABSTRACT The propensity for transspecies prion transmission is related to the structural characteristics of enciphering and new host PrP, although exact mechanism remains incompletely understood. effects variability in protein on cross-species have been studied with animal bioassays, but influence structure versus that cofactors (e.g., cellular constituents, trafficking, innate immune interactions) difficult dissect. To isolate protein-protein interactions conversion, we used recombinant PrP...
Although the unifying hallmark of prion diseases is CNS neurodegeneration caused by conformational corruption host protein (PrP) to its infective counterpart, contagious transmission chronic wasting disease (CWD) results from shedding prions produced at high titers in periphery diseased cervids. While deer and elk PrP primary structures are equivalent except residue 226, which glutamate glutamine deer, effect this difference on CWD pathogenesis largely unknown. Using a gene-targeting...
Chronic wasting disease (CWD), the only known prion endemic in wildlife, is a persistent problem both wild and captive North American cervid populations. This continues to spread cases are found new areas each year. Indirect transmission can occur via environment thought by oral and/or intranasal route. Oral has been experimentally demonstrated although postulated, it not tested natural host until recently. Prions have shown adsorb strongly clay particles upon inoculation prion/clay...
Since prion diseases result from infection and neurodegeneration of the central nervous system (CNS), experimental characterizations strain properties customarily rely on outcomes intracerebral challenges. However, natural transmission certain prions, including those causing chronic wasting disease (CWD) in elk deer, depends propagation peripheral host compartments prior to CNS infection. Using gene-targeted GtE GtQ mice, which accurately control cellular or deer PrP expression, we assessed...
Abstract Background Chronic wasting disease (CWD) in North America is an ineradicable and deadly infectious neurodegenerative disorder of free-ranging captive cervids caused by prions. While CWD was inadvertently introduced to South Korea (SK) following importation sub-clinically diseased elk from America, it unclear whether this event represented a bottleneck infection uncommon prion strain and/or if variant strains evolved during subsequent transmissions additional farmed cervid species...
Prion diseases are a group of incurable neurodegenerative disorders that affect humans and animals via infection with proteinaceous particles called prions. Prions composed PrPSc, misfolded version the cellular prion protein (PrPC). During disease progression, PrPSc replicates by interacting PrPC inducing its conversion to As accumulates, stress mechanisms activated maintain proteostasis, including increased chaperone levels. However, exact roles several these chaperones remain unclear....
The resolution of the three-dimensional structure infectious prions at atomic level is pivotal to understand pathobiology Transmissible Spongiform Encephalopathies (TSE), but has been long hindered due certain particularities these proteinaceous pathogens. Difficulties related their purification from brain homogenates disease-affected animals were resolved almost a decade ago by development in vitro recombinant prion propagation systems giving rise highly prions. However, lack knowledge...
Whereas prion replication involves structural rearrangement of cellular protein (PrP(C)), the existence conformational epitopes remains speculative and controversial, PrP transformation is monitored by immunoblot detection PrP(27-30), a protease-resistant counterpart pathogenic scrapie form (PrP(Sc)) PrP. We now describe involvement specific amino acids in determinants novel monoclonal antibodies (mAbs) raised against randomly chimeric Epitope recognition two mAbs depended on polymorphisms...
The calpain family of calcium-dependent proteases has been implicated in a variety diseases and neurodegenerative pathologies. Prolonged activation calpains results proteolysis numerous cellular substrates including cytoskeletal components membrane receptors, contributing to cell demise despite coincident expression calpastatin, the specific inhibitor calpains. Pharmacological gene-knockout strategies have targeted determine their contribution pathology; however, limitations associated with...
Although they share certain biological properties with nucleic acid based infectious agents, prions, the causative agents of invariably fatal, transmissible neurodegenerative disorders such as bovine spongiform encephalopathy, sheep scrapie, and human Creutzfeldt Jakob disease, propagate by conformational templating host encoded proteins. Once thought to be unique these diseases, this mechanism is now recognized a ubiquitous means information transfer in systems, including other protein...
The causative factors underlying conformational conversion of cellular prion protein (PrPC) into its infectious counterpart (PrPSc) during infection remain undetermined, in part because a lack monoclonal antibodies (mAbs) that can distinguish these isoforms. Here we show the anti-PrP mAb PRC7 recognizes an epitope is shielded from detection when glycans are attached to Asn-196. We observed whereas PrPC predisposed full glycosylation and therefore refractory detection, leads diminished PrPSc...
Protein misfolding cyclic amplification (PMCA) recapitulates the prion protein (PrP) conversion process under cell-free conditions. PMCA was initially established with brain material and then further simplified constituents such as partially purified recombinant PrP. However, availability of from some species or animals certain mutations polymorphisms within PrP gene is often limited. Moreover, preparation native mammalian cells tissues, well bacterial cells, involves time-consuming...
The agent responsible for prion diseases is a misfolded form of normal protein (PrPC). hypothesis stipulates that PrPC must be present the disease to manifest. Cervid populations across world are infected with chronic wasting disease, horizontally-transmissible likely spread via oral exposure infectious prions (PrPCWD). Though PrPCWD has been identified in many tissues, there little effort characterize overall expression cervids and its relationship accumulation. We used immunohistochemistry...
The prevalence, host range and geographical bounds of chronic wasting disease (CWD), the prion cervids, are expanding. Horizontal transmission likely contributes majority new CWD cases, but mechanism by which prions transmitted among CWD-affected cervids remains unclear. To address extent to amplification in peripheral tissues contagious transmission, we assessed levels central nervous lymphoreticular system white-tailed deer (Odocoileus virginianus), red (Cervus elaphus elaphus) elk...
White-tailed deer are susceptible to scrapie (WTD scrapie) after oronasal inoculation with the classical agent from sheep. Deer affected by WTD difficult differentiate infected chronic wasting disease (CWD). To assess transmissibility of and tissue phenotypes when further passaged in white-tailed deer, we oronasally inoculated wild-type agent. We found that CWD agents were generally similar, although some differences noted. The greatest seen bioassays cervidized mice exhibited significantly...
ABSTRACT Mammalian prion diseases are infectious neurodegenerative caused by the self-templating form of protein PrP Sc . Much evidence supports hypothesis that prions exist as a mixture dominant strain and minor strains. While it is known can infect new species, relative contribution strains in crossing species barrier unknown. We previously identified from biologically cloned drowsy (DY) hamster-adapted transmissible mink encephalopathy (TME). Here we show these have increased infection...
Prion agents occur in strains that are encoded by the structure of misfolded prion protein (PrP Sc ). can influence disease phenotype and potential for interspecies transmission. Little is known about transmission prions between sheep deer. Previously, classical US scrapie isolate (No.13-7) had a 100% attack rate white-tailed deer after oronasal challenge. The purpose this study was to test susceptibility challenge with agent passage through (WTD scrapie). Lambs various genotypes were...
Chronic wasting disease (CWD) is a highly infectious prion of cervids. Accumulation prions, the disease-specific structural conformers cellular protein (PrPC), in central nervous system, key pathological event disorder. The analysis cervid PrPC sequences revealed existence polymorphism at position 226, which deer PrP contains glutamine (Q), whereas elk glutamate (E). effects this on CWD are still unknown. We determined high-resolution nuclear magnetic resonance structure mule that was...
Scrapie is a fatal, transmissible neurodegenerative disease that affects sheep and goats. Replication of PrP