Strain-dependent role of copper in prion disease through binding to histidine residues in the N-terminal domain of prion protein.

The cellular prion protein, PrP , is a copper-binding protein abundantly expressed in the brain, particularly by neurons, and its conformational conversion into the amyloidogenic isoform, PrP , plays a key pathogenic role in prion diseases. However, the role of copper binding to PrP in prion diseases remains unclear. Here, we fed mice with a low-copper or regular diet and intracerebrally inoculated them with two different mouse-adapted RML scrapie and BSE prions.

Central residues in prion protein PrP are crucial for its conversion into the pathogenic isoform.

Conformational conversion of the cellular prion protein, PrP, into the amyloidogenic isoform, PrP, is a key pathogenic event in prion diseases. However, the conversion mechanism remains to be elucidated. Here, we generated Tg(PrPΔ91-106)-8545/Prnp mice, which overexpress mouse PrP lacking residues 91-106.

Prion Pathogenesis Revealed in a Series of the Special Issues "Prions and Prion Diseases".

Prion diseases are a group of devastating neurodegenerative disorders, which include Creutzfeldt-Jakob disease (CJD) in humans, and scrapie and bovine spongiform encephalopathy (BSE) in animals [...

The first non-prion pathogen identified: neurotropic influenza virus.

The cellular isoform of prion protein, designated PrP, is a membrane glycoprotein expressed most abundantly in the brain, particularly by neurons, and its conformational conversion into the abnormally folded, amyloidogenic isoform, PrP, is an underlying mechanism in the pathogenesis of prion diseases, a group of neurodegenerative disorders in humans and animals. Most cases of these diseases are sporadic and their aetiologies are unknown. We recently found that a neurotropic strain of influenza A virus (IAV/WSN) caused the conversion of PrP into PrP and the subsequent formation of infectious prions in mouse neuroblastoma cells after infection.

Virus Infection, Genetic Mutations, and Prion Infection in Prion Protein Conversion.

Conformational conversion of the cellular isoform of prion protein, PrP, into the abnormally folded, amyloidogenic isoform, PrP, is an underlying pathogenic mechanism in prion diseases. The diseases manifest as sporadic, hereditary, and acquired disorders. Etiological mechanisms driving the conversion of PrP into PrP are unknown in sporadic prion diseases, while prion infection and specific mutations in the PrP gene are known to cause the conversion of PrP into PrP in acquired and hereditary prion diseases, respectively.

Ethanolamine Is a New Anti-Prion Compound.

Prion diseases are a group of fatal neurodegenerative disorders caused by accumulation of proteinaceous infectious particles, or prions, which mainly consist of the abnormally folded, amyloidogenic prion protein, designated PrP. PrP is produced through conformational conversion of the cellular isoform of prion protein, PrP, in the brain. To date, no effective therapies for prion diseases have been developed.

Neurotropic influenza A virus infection causes prion protein misfolding into infectious prions in neuroblastoma cells.

Misfolding of the cellular prion protein, PrP, into the amyloidogenic isoform, PrP, which forms infectious protein aggregates, the so-called prions, is a key pathogenic event in prion diseases. No pathogens other than prions have been identified to induce misfolding of PrP into PrP and propagate infectious prions in infected cells. Here, we found that infection with a neurotropic influenza A virus strain (IAV/WSN) caused misfolding of PrP into PrP and generated infectious prions in mouse neuroblastoma cells through a hit-and-run mechanism.

Vaporized Hydrogen Peroxide and Ozone Gas Synergistically Reduce Prion Infectivity on Stainless Steel Wire.

Prions are infectious agents causing prion diseases, which include Creutzfeldt-Jakob disease (CJD) in humans. Several cases have been reported to be transmitted through medical instruments that were used for preclinical CJD patients, raising public health concerns on iatrogenic transmissions of the disease. Since preclinical CJD patients are currently difficult to identify, medical instruments need to be adequately sterilized so as not to transmit the disease.

Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91-106.

Conformational conversion of the cellular prion protein, PrP, into the abnormally folded isoform, PrP, is a key pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Transgenic mice expressing PrP with a deletion of the central residues 91-106 were generated in the absence of endogenous PrP, designated Tg(PrP∆91-106)/ mice and intracerebrally inoculated with various prions.

Impairment of cerebellar long-term depression and GABAergic transmission in prion protein deficient mice ectopically expressing PrPLP/Dpl.

Prion protein (PrP) knockout mice, named as the "Ngsk" strain (Ngsk Prnp mice), show late-onset cerebellar Purkinje cell (PC) degeneration because of ectopic overexpression of PrP-like protein (PrPLP/Dpl). Our previous study indicated that the mutant mice also exhibited alterations in cerebellum-dependent delay eyeblink conditioning, even at a young age (16 weeks of age) when neurological changes had not occurred. Thus, this electrophysiological study was designed to examine the synaptic function of the cerebellar cortex in juvenile Ngsk Prnp mice.

N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases.

The normal cellular isoform of prion protein, designated PrP, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrP, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrP is a membrane glycoprotein consisting of the non-structural -terminal domain and the globular C-terminal domain. During conversion of PrP to PrP, its 2/3 C-terminal region undergoes marked structural changes, forming a protease-resistant structure.

Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice.

The cellular prion protein, PrPC, is a glycosylphosphatidylinositol anchored-membrane glycoprotein expressed most abundantly in neuronal and to a lesser extent in non-neuronal cells. Its conformational conversion into the amyloidogenic isoform in neurons is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. However, the normal functions of PrPC remain largely unknown, particularly in non-neuronal cells.

Prion Protein is a Novel Modulator of Influenza: Potential Implications for Anti-Influenza Therapeutics.

Worldwide spread of influenza A virus (IAV) strains, which are resistant to currently available anti- influenza agents such as viral neuraminidase inhibitors, has encouraged identification of new target molecules for anti-influenza agents. Reactive oxygen species (ROS) causing oxidative stress play a pivotal role in the pathogenesis of lung injuries induced by infection with IAVs, therefore suggesting that anti-oxidative therapeutics targeting cellular molecules could be beneficial against IAV infection without inducing drug-resistant IAV strains. We recently found that the normal cellular prion protein, PrP, whose conformational conversion into the amyloidogenic isoform, PrP, in the brain is a key pathogenic event in prion diseases, is expressed by lung epithelial cells and exerts a protective role against IAV infection in mice by reducing ROS in infected lungs.

Roles of Prion Protein in Virus Infections.

The normal cellular prion protein, designated PrP, is a membrane glycoprotein expressed most abundantly in brains, particularly by neurons, and to a lesser extent in non-neuronal tissues including lungs. Conformational conversion of PrP into the amyloidogenic isoform is a key pathogenic event in prion diseases. We recently found that PrP has a protective role against infection with influenza A viruses (IAVs) in mice by reducing reactive oxygen species in the lungs after infection with IAVs.

Prion protein protects mice from lethal infection with influenza A viruses.

The cellular prion protein, designated PrPC, is a membrane glycoprotein expressed abundantly in brains and to a lesser extent in other tissues. Conformational conversion of PrPC into the amyloidogenic isoform is a key pathogenic event in prion diseases. However, the physiological functions of PrPC remain largely unknown, particularly in non-neuronal tissues.

Novel amplification mechanism of prions through disrupting sortilin-mediated trafficking.

Conformational conversion of the cellular prion protein, PrP, into the abnormally folded isoform of prion protein, PrP, which leads to marked accumulation of PrP in brains, is a key pathogenic event in prion diseases, a group of fatal neurodegenerative disorders caused by prions. However, the exact mechanism of PrP accumulation in prion-infected neurons remains unknown. We recently reported a novel cellular mechanism to support PrP accumulation in prion-infected neurons, in which PrP itself promotes its accumulation by evading the cellular inhibitory mechanism, which is newly identified in our recent study.

Prion Protein Devoid of the Octapeptide Repeat Region Delays Bovine Spongiform Encephalopathy Pathogenesis in Mice.

Conformational conversion of the cellular isoform of prion protein, PrP, into the abnormally folded, amyloidogenic isoform, PrP, is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals. We previously reported that the octapeptide repeat (OR) region could be dispensable for converting PrP into PrP after infection with RML prions. We demonstrated that mice transgenically expressing mouse PrP with deletion of the OR region on the PrP knockout background, designated Tg(PrPΔOR)/ mice, did not show reduced susceptibility to RML scrapie prions, with abundant accumulation of PrPΔOR in their brains.

Prions amplify through degradation of the VPS10P sorting receptor sortilin.

Prion diseases are a group of fatal neurodegenerative disorders caused by prions, which consist mainly of the abnormally folded isoform of prion protein, PrPSc. A pivotal pathogenic event in prion disease is progressive accumulation of prions, or PrPSc, in brains through constitutive conformational conversion of the cellular prion protein, PrPC, into PrPSc. However, the cellular mechanism by which PrPSc is progressively accumulated in prion-infected neurons remains unknown.

Effects of prion protein devoid of the N-terminal residues 25-50 on prion pathogenesis in mice.

The N-terminal polybasic region of the normal prion protein, PrP, which encompasses residues 23-31, is important for prion pathogenesis by affecting conversion of PrP into the pathogenic isoform, PrP. We previously reported transgenic mice expressing PrP with residues 25-50 deleted in the PrP-null background, designated as Tg(PrP∆preOR)/Prnp mice. Here, we produced two new lines of Tg(PrP∆preOR)/Prnp mice, each expressing the mutant protein, PrP∆preOR, 1.

Melanin or a Melanin-Like Substance Interacts with the N-Terminal Portion of Prion Protein and Inhibits Abnormal Prion Protein Formation in Prion-Infected Cells.

Prion diseases are progressive fatal neurodegenerative illnesses caused by the accumulation of transmissible abnormal prion protein (PrP). To find treatments for prion diseases, we searched for substances from natural resources that inhibit abnormal PrP formation in prion-infected cells. We found that high-molecular-weight components from insect cuticle extracts reduced abnormal PrP levels.

Mouse-hamster chimeric prion protein (PrP) devoid of N-terminal residues 23-88 restores susceptibility to 22L prions, but not to RML prions in PrP-knockout mice.

Prion infection induces conformational conversion of the normal prion protein PrPC, into the pathogenic isoform PrPSc, in prion diseases. It has been shown that PrP-knockout (Prnp0/0) mice transgenically reconstituted with a mouse-hamster chimeric PrP lacking N-terminal residues 23-88, or Tg(MHM2Δ23-88)/Prnp 0/0 mice, neither developed the disease nor accumulated MHM2ScΔ23-88 in their brains after inoculation with RML prions. In contrast, RML-inoculated Tg(MHM2Δ23-88)/Prnp 0/+ mice developed the disease with abundant accumulation of MHM2ScΔ23-88 in their brains.

Disturbed vesicular trafficking of membrane proteins in prion disease.

The pathogenic mechanism of prion diseases remains unknown. We recently reported that prion infection disturbs post-Golgi trafficking of certain types of membrane proteins to the cell surface, resulting in reduced surface expression of membrane proteins and abrogating the signal from the proteins. The surface expression of the membrane proteins was reduced in the brains of mice inoculated with prions, well before abnormal symptoms became evident.