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原英之

徳島大学

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2025年8月29日更新

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学歴: 2005/3: 東京大学大学院医学系研究科博士課程修了
学位: 博士 / 博士(医学) (東京大学) (2005年3月)
職歴・経歴: 2005/4: 東京大学医科学研究所基礎医科学部門遺伝子動態分野研究員
2007/4: 国立感染症研究所細胞化学部研究員

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論文

Hideyuki Hara, Junji Chida, Batzaya Batchuluun, Etsuhisa Takahashi, Hiroshi Kido and Suehiro Sakaguchi :
Protective Role of Cytosolic Prion Protein against Virus Infection in Prion-Infected Cells.,
Journal of Virology, 98, 9, e0126224, 2024.

(要約): Production of the amyloidogenic prion protein, PrP, which forms infectious protein aggregates, or prions, is a key pathogenic event in prion diseases. Functional prion-like protein aggregations, such as the mitochondrial adaptor protein MAVS and the inflammasome component protein ASC, have been identified to play a protective role in viral infections in mammalian cells. In this study, to investigate if PrP could play a functional role against external stimuli, we infected prion-infected cells with a neurotropic influenza A virus strain, IAV/WSN. We found that prion-infected cells were highly resistant to IAV/WSN infection. In these cells, NF-κB nuclear translocation was disturbed; therefore, mitochondrial superoxide dismutase (mtSOD) expression was suppressed, and mitochondrial reactive oxygen species (mtROS) was increased. The elevated mtROS subsequently activated NLRP3 inflammasomes, leading to the suppression of IAV/WSN-induced necroptosis. We also found that prion-infected cells accumulated a portion of PrP molecules in the cytosol, and that the N-terminal potential nuclear translocation signal of PrP impeded NF-κB nuclear translocation. These results suggest that PrP might play a functional role in protection against viral infections by stimulating the NLRP3 inflammasome-dependent antivirus mechanism through the cytosolic PrP-mediated disturbance of NF-κB nuclear translocation, which leads to suppression of mtSOD expression and consequently upregulation of the NLRP3 inflammasome activator mtROS. Cytosolic PrP has been detected in prion-infected cells and suggested to be involved in the neurotoxicity of prions. Here, we also detected cytosolic PrP in prion-infected cells. We further found that the nuclear translocation of NF-κB was disturbed in prion-infected cells and that the N-terminal potential nuclear translocation signal of PrP expressed in the cytosol disturbed the nuclear translocation of NF-κB. Thus, the N-terminal nuclear translocation signal of cytosolic PrP might play a role in prion neurotoxicity. Prion-like protein aggregates in other protein misfolding disorders, including Alzheimer's disease were reported to play a protective role against various environmental stimuli. We here showed that prion-infected cells were partially resistant to IAV/WSN infection due to the cytosolic PrP-mediated disturbance of the nuclear translocation of NF-κB, which consequently activated NLRP3 inflammasomes after IAV/WSN infection. It is thus possible that prions could also play a protective role in viral infections.
(キーワード): Animals / Cytosol / NLR Family, Pyrin Domain-Containing 3 Protein / Inflammasomes / NF-kappa B / Reactive Oxygen Species / Mice / Humans / Mitochondria / PrPSc Proteins / Prion Diseases / Cell Line / Superoxide Dismutase / Prions / Prion Proteins / Necroptosis
(出版サイトへのリンク): ● Publication site (DOI): 10.1128/jvi.01262-24
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39194237; ● Search Scopus @ Elsevier (PMID): 39194237; ● Search Scopus @ Elsevier (DOI): 10.1128/jvi.01262-24

(DOI: 10.1128/jvi.01262-24, PubMed: 39194237) Hideyuki Hara, Hironori Miyata, Junji Chida and Suehiro Sakaguchi :
Strain-Dependent Role of Copper in Prion Disease through Binding to Histidine Residues in the N-Terminal Domain of Prion Protein.,
Journal of Neurochemistry, 167, 3, 394-409, 2023.

(要約): 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. Mice with a low-copper diet developed disease significantly but only slightly later than those with a regular diet after inoculation with BSE prions, but not with RML prions, suggesting that copper could play a minor role in BSE prion pathogenesis, but not in RML prion pathogenesis. We then generated two lines of transgenic mice expressing mouse PrP with copper-binding histidine (His) residues in the N-terminal domain replaced with alanine residues, termed TgPrP(5H > A)-7342/Prnp and TgPrP(5H > A)-7524/Prnp mice, and similarly inoculated RML and BSE prions into them. Due to 2-fold higher expression of PrP(5H > A) than PrP in wild-type (WT) mice, TgPrP(5H > A)-7524/Prnp mice were highly susceptible to these prions, compared to WT mice. However, TgPrP(5H > A)-7342/Prnp mice, which express PrP(5H > A) 1.2-fold as high as PrP in WT mice, succumbed to disease slightly, but not significantly, later than WT mice after inoculation with RML prions, but significantly so after inoculation with BSE prions. Subsequent secondary inoculation experiments revealed that amino acid sequence differences between PrP(5H > A) and WT PrP created no prion transmission barrier to BSE prions. These results suggest that copper-binding His residues in PrP are dispensable for RML prion pathogenesis but have a minor effect on BSE prion pathogenesis. Taken together, our current results suggest that copper could have a minor effect on prion pathogenesis in a strain-dependent manner through binding to His residues in the N-terminal domain of PrP .
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/jnc.15971
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37777338; ● Search Scopus @ Elsevier (PMID): 37777338; ● Search Scopus @ Elsevier (DOI): 10.1111/jnc.15971

(DOI: 10.1111/jnc.15971, PubMed: 37777338) Suehiro Sakaguchi and Hideyuki Hara :
The first non-prion pathogen identified: neurotropic influenza virus.,
Prion, 16, 1, 1-6, 2022.

(徳島大学機関リポジトリ): ● Metadata: 2010395
(出版サイトへのリンク): ● Publication site (DOI): 10.1080/19336896.2021.2015224
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34978525; ● Search Scopus @ Elsevier (PMID): 34978525; ● Search Scopus @ Elsevier (DOI): 10.1080/19336896.2021.2015224

(徳島大学機関リポジトリ: 2010395, DOI: 10.1080/19336896.2021.2015224, PubMed: 34978525) Dini Agriani Pasiana, Hironori Miyata, Junji Chida, Hideyuki Hara, Morikazu Imamura, Ryuichiro Atarashi and Suehiro Sakaguchi :
Central residues in prion protein PrPC are crucial for its conversion into the pathogenic isoform,
The Journal of Biological Chemistry, 298, 9, 102381, 2022.

(キーワード): prion / Mice / Prion Diseases / Prion Proteins
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jbc.2022.102381
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 35973512; ● Search Scopus @ Elsevier (PMID): 35973512; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jbc.2022.102381

(DOI: 10.1016/j.jbc.2022.102381, PubMed: 35973512) Hideyuki Hara and Suehiro Sakaguchi :
Virus Infection, Genetic Mutations, and Prion Infection in Prion Protein Conversion.,
International Journal of Molecular Sciences, 22, 22, 12439, 2021.

(徳島大学機関リポジトリ): ● Metadata: 2010354
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/ijms222212439
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34830321; ● Search Scopus @ Elsevier (PMID): 34830321; ● Search Scopus @ Elsevier (DOI): 10.3390/ijms222212439

(徳島大学機関リポジトリ: 2010354, DOI: 10.3390/ijms222212439, PubMed: 34830321) Keiji Uchiyama, Hideyuki Hara, Junji Chida, Agriani Dini Pasiana, Morikazu Imamura, Tsuyoshi Mori, Hanae Takatsuki, Ryuichiro Atarashi and Suehiro Sakaguchi :
Ethanolamine Is a New Anti-Prion Compound,
International Journal of Molecular Sciences, 22, 21, 11742, 2021.

(要約): 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. In this study, we incidentally noticed that mouse neuroblastoma N2a cells persistently infected with 22L scrapie prions, termed N2aC24L1-3 cells, reduced PrP levels when cultured in advanced Dulbecco's modified eagle medium (DMEM) but not in classic DMEM. PrP levels remained unchanged in prion-uninfected parent N2aC24 cells cultured in advanced DMEM. These results suggest that advanced DMEM may contain an anti-prion compound(s). We then successfully identified ethanolamine in advanced DMEM has an anti-prion activity. Ethanolamine reduced PrP levels in N2aC24L1-3 cells, but not PrP levels in N2aC24 cells. Also, oral administration of ethanolamine through drinking water delayed prion disease in mice intracerebrally inoculated with RML scrapie prions. These results suggest that ethanolamine could be a new anti-prion compound.
(キーワード): Animals / Brain / Cell Line, Tumor / Ethanolamine / Mice / Mice, Inbred ICR / PrPSc Proteins / Prion Diseases
(徳島大学機関リポジトリ): ● Metadata: 2010355
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/ijms222111742
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34769172; ● Summary page in Scopus @ Elsevier: 2-s2.0-85118175726

(徳島大学機関リポジトリ: 2010355, DOI: 10.3390/ijms222111742, PubMed: 34769172, Elsevier: Scopus) Hideyuki Hara, Junji Chida, Keiji Uchiyama, Dini Agriani Pasiana, Etsuhisa Takahashi, Hiroshi Kido and Suehiro Sakaguchi :
Neurotropic influenza A virus infection causes prion protein misfolding into infectious prions in neuroblastoma cells.,
Scientific Reports, 11, 1, 10109, 2021.

(徳島大学機関リポジトリ): ● Metadata: 2010515
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s41598-021-89586-6
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33980968; ● Summary page in Scopus @ Elsevier: 2-s2.0-85105825147; ● Summary page in Scopus @ Elsevier: 2-s2.0-105004346341

(徳島大学機関リポジトリ: 2010515, DOI: 10.1038/s41598-021-89586-6, PubMed: 33980968, Elsevier: Scopus, Elsevier: Scopus) Hideyuki Hara, Junji Chida, Agriani Dini Pasiana, Keiji Uchiyama, Yutaka Kikuchi, Tomoko Naito, Yuichi Takahashi, Junji Yamamura, Hisashi Kuromatsu and Suehiro Sakaguchi :
Vaporized Hydrogen Peroxide and Ozone Gas Synergistically Reduce Prion Infectivity on Stainless Steel Wire.,
International Journal of Molecular Sciences, 22, 6, 3268, 2021.

(要約): 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. In this study, we investigated the sterilizing activity of two oxidizing agents, ozone gas and vaporized hydrogen peroxide, against prions fixed on stainless steel wires using a mouse bioassay. Mice intracerebrally implanted with prion-contaminated stainless steel wires treated with ozone gas or vaporized hydrogen peroxide developed prion disease later than those implanted with control prion-contaminated stainless steel wires, indicating that ozone gas and vaporized hydrogen peroxide could reduce prion infectivity on wires. Incubation times were further elongated in mice implanted with prion-contaminated stainless steel wires treated with ozone gas-mixed vaporized hydrogen peroxide, indicating that ozone gas mixed with vaporized hydrogen peroxide reduces prions on these wires more potently than ozone gas or vaporized hydrogen peroxide. These results suggest that ozone gas mixed with vaporized hydrogen peroxide might be more useful for prion sterilization than ozone gas or vaporized hydrogen peroxide alone.
(キーワード): Animals / Brain / Disease Models, Animal / Dose-Response Relationship, Drug / Hydrogen Peroxide / Mice / Ozone / PrPC Proteins / Prion Diseases / Prions / Stainless Steel
(徳島大学機関リポジトリ): ● Metadata: 2009255
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/ijms22063268
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33806892; ● Summary page in Scopus @ Elsevier: 2-s2.0-85102845949

(徳島大学機関リポジトリ: 2009255, DOI: 10.3390/ijms22063268, PubMed: 33806892, Elsevier: Scopus) Keiji Uchiyama, Miyata Hironori, Yamaguchi Yoshitaka, Imamura Morikazu, Okazaki Mariya, Pasiana Dini Agriani, Junji Chida, Hideyuki Hara, Atarashi Ryuichiro, Watanabe Hitomi, Kondoh Gen and Suehiro Sakaguchi :
Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91-106.,
International Journal of Molecular Sciences, 21, 19, 7260, 2020.

(要約): 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. Tg(PrP∆91-106)/ mice were resistant to RML, 22L and FK-1 prions, neither producing PrP∆91-106 or prions in the brain nor developing disease after inoculation. However, they remained marginally susceptible to bovine spongiform encephalopathy (BSE) prions, developing disease after elongated incubation times and accumulating PrP∆91-106 and prions in the brain after inoculation with BSE prions. Recombinant PrP∆91-104 converted into PrP∆91-104 after incubation with BSE-PrP-prions but not with RML- and 22L-PrP-prions, in a protein misfolding cyclic amplification assay. However, digitonin and heparin stimulated the conversion of PrP∆91-104 into PrP∆91-104 even after incubation with RML- and 22L-PrP-prions. These results suggest that residues 91-106 or 91-104 of PrP are crucially involved in prion pathogenesis in a strain-dependent manner and may play a similar role to digitonin and heparin in the conversion of PrP into PrP.
(徳島大学機関リポジトリ): ● Metadata: 2008559
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/ijms21197260
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33019549; ● Summary page in Scopus @ Elsevier: 2-s2.0-85091919621

(徳島大学機関リポジトリ: 2008559, DOI: 10.3390/ijms21197260, PubMed: 33019549, Elsevier: Scopus) Hideyuki Hara and Suehiro Sakaguchi :
N-terminal Regions of Prion Protein: Functions and Roles in Prion Diseases.,
International Journal of Molecular Sciences, 21, 17, E6233, 2020.

(要約): 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. In contrast, the N-terminal region remains protease-sensitive in PrP. Reverse genetic studies using reconstituted PrP-knockout mice with various mutant PrP molecules have revealed that the N-terminal domain has an important role in the normal function of PrP and the conversion of PrP to PrP. The N-terminal domain includes various characteristic regions, such as the positively charged residue-rich polybasic region, the octapeptide repeat (OR) region consisting of five repeats of an octapeptide sequence, and the post-OR region with another positively charged residue-rich polybasic region followed by a stretch of hydrophobic residues. We discuss the normal functions of PrP, the conversion of PrP to PrP, and the neurotoxicity of PrP by focusing on the roles of the N-terminal regions in these topics.
(徳島大学機関リポジトリ): ● Metadata: 2008558
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/ijms21176233
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32872280; ● Summary page in Scopus @ Elsevier: 2-s2.0-85090181761

(徳島大学機関リポジトリ: 2008558, DOI: 10.3390/ijms21176233, PubMed: 32872280, Elsevier: Scopus) Junji Chida, Hideyuki Hara, Keiji Uchiyama, Etsuhisa Takahashi, Hironori Miyata, Hidetaka Kosako, Yukiko Tomioka, Toshihiro Ito, Hiroyuki Horiuchi, Haruo Matsuda, Hiroshi Kido and Suehiro Sakaguchi :
Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice.,
PLoS Pathogens, 16, 8, e1008823, 2020.

(要約): 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. Here we show that stimulation of PrPC with anti-PrP monoclonal antibodies (mAbs) protected mice from lethal infection with influenza A viruses (IAVs), with abundant accumulation of anti-inflammatory M2 macrophages with activated Src family kinases (SFKs) in infected lungs. A SFK inhibitor dasatinib inhibited M2 macrophage accumulation in IAV-infected lungs after treatment with anti-PrP mAbs and abolished the anti-PrP mAb-induced protective activity against lethal influenza infection in mice. We also show that stimulation of PrPC with anti-PrP mAbs induced M2 polarization in peritoneal macrophages through SFK activation in vitro and in vivo. These results indicate that PrPC could activate SFK in macrophages and induce macrophage polarization to an anti-inflammatory M2 phenotype after stimulation with anti-PrP mAbs, thereby eliciting protective activity against lethal infection with IAVs in mice after treatment with anti-PrP mAbs. These results also highlight PrPC as a novel therapeutic target for IAV infection.
(徳島大学機関リポジトリ): ● Metadata: 2008538
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.ppat.1008823
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32845931; ● Search Scopus @ Elsevier (PMID): 32845931; ● Search Scopus @ Elsevier (DOI): 10.1371/journal.ppat.1008823

(徳島大学機関リポジトリ: 2008538, DOI: 10.1371/journal.ppat.1008823, PubMed: 32845931) Nandita Rani Das, Hironori Miyata, Hideyuki Hara, Junji Chida, Keiji Uchiyama, Kentaro Masujin, Hitomi Watanabe, Gen Kondoh and Suehiro Sakaguchi :
The N-Terminal Polybasic Region of Prion Protein Is Crucial in Prion Pathogenesis Independently of the Octapeptide Repeat Region,
Molecular Neurobiology, 57, 1203-1216, 2019.

(要約): Conformational conversion of the cellular isoform of prion protein, designated PrP, into the abnormally folded, amyloidogenic isoform, PrP, is an essential pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Lines of evidence indicate that the N-terminal domain, which includes the N-terminal, positively charged polybasic region and the octapeptide repeat (OR) region, is important for PrP to convert into PrP after infection with prions. To further gain insights into the role of the polybasic region and the OR region in prion pathogenesis, we generated two different transgenic mice, designated Tg(PrP3K3A)/Prnp and Tg(PrP3K3A∆OR)/Prnp mice, which express PrP with lysine residues at codons 23, 24, and 27 in the polybasic region mutated with or without a deletion of the OR region on the Prnp background, respectively, and intracerebrally inoculated them with RML and 22L prions. We show that Tg(PrP3K3A)/Prnp mice were highly resistant to the prions, indicating that lysine residues at 23, 24, and 27 could be important for the polybasic region to support prion infection. Tg(PrP3K3A∆OR)/Prnp mice also had reduced susceptibility to RML and 22L prions equivalent to Tg(PrP3K3A)/Prnp mice. The pre-OR region, including the polybasic region, of PrP3K3A∆OR, but not PrP3K3A, was unusually converted to a protease-resistant structure during conversion to PrP3K3A∆OR. These results suggest that, while the OR region could affect the conformation of the polybasic region during conversion of PrP into PrP, the polybasic region could play a crucial role in prion pathogenesis independently of the OR region.
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s12035-019-01804-5
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31707632; ● Summary page in Scopus @ Elsevier: 2-s2.0-85074844020

(DOI: 10.1007/s12035-019-01804-5, PubMed: 31707632, Elsevier: Scopus) Ken'ichi Hagiwara, Yuko Sato, Yoshio Yamakawa, Hideyuki Hara, Minoru Tobiume, Yuko Okemoto-Nakamura, Tetsutaro Sata, Motohiro Horiuchi, Hiroaki Shibata and Fumiko Ono :
Tracking and clarifying differential traits of classical- and atypical L-type bovine spongiform encephalopathy prions after transmission from cattle to cynomolgus monkeys.,
PLoS ONE, 14, 5, e0216807, 2019.

(要約): Classical- (C-) and atypical L-type bovine spongiform encephalopathy (BSE) prions cause different pathological phenotypes in cattle brains, and the disease-associated forms of each prion protein (PrPSc) has a dissimilar biochemical signature. Bovine C-BSE prions are the causative agent of variant Creutzfeldt-Jakob disease. To date, human infection with L-BSE prions has not been reported, but they can be transmitted experimentally from cows to cynomolgus monkeys (Macaca fascicularis), a non-human primate model. When transmitted to monkeys, C- and L-BSE prions induce different pathological phenotypes in the brain. However, when isolated from infected brains, the two prion proteins (PrPSc) have similar biochemical signatures (i.e., electrophoretic mobility, glycoforms, and resistance to proteinase K). Such similarities suggest the possibility that L-BSE prions alter their virulence to that of C-BSE prions during propagation in monkeys. To clarify this possibility, we conducted bioassays using inbred mice. C-BSE prions with or without propagation in monkeys were pathogenic to mice, and exhibited comparable incubation periods in secondary passage in mice. By contrast, L-BSE prions, either with or without propagation in monkeys, did not cause the disease in mice, indicating that the pathogenicity of L-BSE prions does not converge towards a C-BSE prion type in this primate model. These results suggest that, although C- and L-BSE prions propagated in cynomolgus monkeys exhibit similar biochemical PrPSc signatures and consist of the monkey amino acid sequence, the two prions maintain strain-specific conformations of PrPSc in which they encipher and retain unique pathogenic traits.
(キーワード): Animals / Brain / Cattle / Encephalopathy, Bovine Spongiform / Female / Humans / Macaca fascicularis / Mice / Prions
(徳島大学機関リポジトリ): ● Metadata: 2007304
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.pone.0216807
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31095605; ● Summary page in Scopus @ Elsevier: 2-s2.0-85065922755

(徳島大学機関リポジトリ: 2007304, DOI: 10.1371/journal.pone.0216807, PubMed: 31095605, Elsevier: Scopus) Junji Chida, Hideyuki Hara, Masashi Yano, Keiji Uchiyama, Rani Nandita Das, Etsuhisa Takahashi, Hironori Miyata, Yukiko Tomioka, Toshihiro Ito, Hiroshi Kido and Suehiro Sakaguchi :
Prion protein protects mice from lethal infection with influenza A viruses.,
PLoS Pathogens, 14, 5, e1007049, 2018.

(要約): 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. Here, we show that PrPC is expressed in lung epithelial cells, including alveolar type 1 and 2 cells and bronchiolar Clara cells. Compared with wild-type (WT) mice, PrPC-null mice (Prnp0/0) were highly susceptible to influenza A viruses (IAVs), with higher mortality. Infected Prnp0/0 lungs were severely injured, with higher inflammation and higher apoptosis of epithelial cells, and contained higher reactive oxygen species (ROS) than control WT lungs. Treatment with a ROS scavenger or an inhibitor of xanthine oxidase (XO), a major ROS-generating enzyme in IAV-infected lungs, rescued Prnp0/0 mice from the lethal infection with IAV. Moreover, Prnp0/0 mice transgenic for PrP with a deletion of the Cu-binding octapeptide repeat (OR) region, Tg(PrPOR)/Prnp0/0 mice, were also highly susceptible to IAV infection. These results indicate that PrPC has a protective role against lethal infection with IAVs through the Cu-binding OR region by reducing ROS in infected lungs. Cu content and the activity of anti-oxidant enzyme Cu/Zn-dependent superoxide dismutase, SOD1, were lower in Prnp0/0 and Tg(PrPOR)/Prnp0/0 lungs than in WT lungs. It is thus conceivable that PrPC functions to maintain Cu content and regulate SOD1 through the OR region in lungs, thereby reducing ROS in IAV-infected lungs and eventually protecting them from lethal infection with IAVs. Our current results highlight the role of PrPC in protection against IAV infection, and suggest that PrPC might be a novel target molecule for anti-influenza therapeutics.
(キーワード): Animals / Brain / Copper / Disease Susceptibility / Influenza A virus / Lung / Mice / Mice, Inbred C57BL / Mice, Knockout / Neurons / PrPC Proteins / Prion Diseases / Prion Proteins / Prions / Reactive Oxygen Species / Superoxide Dismutase
(徳島大学機関リポジトリ): ● Metadata: 2005362
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.ppat.1007049
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29723291; ● Search Scopus @ Elsevier (PMID): 29723291; ● Search Scopus @ Elsevier (DOI): 10.1371/journal.ppat.1007049

(徳島大学機関リポジトリ: 2005362, DOI: 10.1371/journal.ppat.1007049, PubMed: 29723291) Hideyuki Hara, Hironori Miyata, Das Rani Nandita, Junji Chida, Tatenobu Yoshimochi, Keiji Uchiyama, Hitomi Watanabe, Gen Kondoh, Takashi Yokoyama and Suehiro Sakaguchi :
Prion Protein Devoid of the Octapeptide Repeat Region Delays BSE Pathogenesis in Mice.,
Journal of Virology, 92, 1, pii:e01368-17, 2018.

(要約): 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. We show here that Tg(PrPΔOR)/ mice were highly resistant to BSE prions, developing the disease with markedly elongated incubation times after infection with BSE prions. The conversion of PrPΔOR into PrPΔOR was markedly delayed in their brains. These results suggest that the OR region may have a crucial role in the conversion of PrP into PrP after infection with BSE prions. However, Tg(PrPΔOR)/ mice remained susceptible to RML and 22L scrapie prions, developing the disease without elongated incubation times after infection with RML and 22L prions. PrPΔOR accumulated only slightly less in the brains of RML- or 22L-infected Tg(PrPΔOR)/ mice than PrP in control wild-type mice. Taken together, these results indicate that the OR region of PrP could play a differential role in the pathogenesis of BSE prions and RML or 22L scrapie prions. Structure-function relationship studies of PrP conformational conversion into PrP are worthwhile to understand the mechanism of the conversion of PrP into PrP We show here that, by inoculating Tg(PrPΔOR)/ mice with the three different strains of RML, 22L, and BSE prions, the OR region could play a differential role in the conversion of PrP into PrP after infection with RML or 22L scrapie prions and BSE prions. PrPΔOR was efficiently converted into PrPΔOR after infection with RML and 22L prions. However, the conversion of PrPΔOR into PrPΔOR was markedly delayed after infection with BSE prions. Further investigation into the role of the OR region in the conversion of PrP into PrP after infection with BSE prions might be helpful for understanding the pathogenesis of BSE prions.
(キーワード): Animals / 脳 (brain) / Cattle / Disease Susceptibility / Encephalopathy, Bovine Spongiform / Humans / Mice / トランスジェニックマウス (transgenic mice) / Oligopeptides / PrPC Proteins / Prion Diseases / Prions / Sequence Deletion
(徳島大学機関リポジトリ): ● Metadata: 2004644
(出版サイトへのリンク): ● Publication site (DOI): 10.1128/JVI.01368-17
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29046443; ● CiNii @ 国立情報学研究所 (CRID): 1050867133852477440; ● Search Scopus @ Elsevier (PMID): 29046443; ● Search Scopus @ Elsevier (DOI): 10.1128/JVI.01368-17

(徳島大学機関リポジトリ: 2004644, DOI: 10.1128/JVI.01368-17, PubMed: 29046443, CiNii: 1050867133852477440) Keiji Uchiyama, Mitsuru Tomita, Masashi Yano, Junji Chida, Hideyuki Hara, Nandita Rani Das, Anders Nykjaer and Suehiro Sakaguchi :
Prions amplify through degradation of the VPS10P sorting receptor sortilin.,
PLoS Pathogens, 13, 6, e1006470, 2017.

(要約): 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. Here, we show that PrPSc is progressively accumulated in prion-infected cells through degradation of the VPS10P sorting receptor sortilin. We first show that sortilin interacts with PrPC and PrPSc and sorts them to lysosomes for degradation. Consistently, sortilin-knockdown increased PrPSc accumulation in prion-infected cells. In contrast, overexpression of sortilin reduced PrPSc accumulation in prion-infected cells. These results indicate that sortilin negatively regulates PrPSc accumulation in prion-infected cells. The negative role of sortilin in PrPSc accumulation was further confirmed in sortilin-knockout mice infected with prions. The infected mice had accelerated prion disease with early accumulation of PrPSc in their brains. Interestingly, sortilin was reduced in prion-infected cells and mouse brains. Treatment of prion-infected cells with lysosomal inhibitors, but not proteasomal inhibitors, increased the levels of sortilin. Moreover, sortilin was reduced following PrPSc becoming detectable in cells after infection with prions. These results indicate that PrPSc accumulation stimulates sortilin degradation in lysosomes. Taken together, these results show that PrPSc accumulation of itself could impair the sortilin-mediated sorting of PrPC and PrPSc to lysosomes for degradation by stimulating lysosomal degradation of sortilin, eventually leading to progressive accumulation of PrPSc in prion-infected cells.
(キーワード): prion / Sortilin / VPS10P
(徳島大学機関リポジトリ): ● Metadata: 2003631
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.ppat.1006470
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28665987; ● Search Scopus @ Elsevier (PMID): 28665987; ● Search Scopus @ Elsevier (DOI): 10.1371/journal.ppat.1006470

(徳島大学機関リポジトリ: 2003631, DOI: 10.1371/journal.ppat.1006470, PubMed: 28665987) Das Rani Nandita, Miyata Hironori, Hideyuki Hara, Keiji Uchiyama, Junji Chida, Masashi Yano, Watanabe Hitomi, Kondoh Gen and Suehiro Sakaguchi :
Effects of prion protein devoid of the N-terminal residues 25-50 on prion pathogenesis in mice.,
Archives of Virology, 162, 7, 1867-1876, 2017.

(要約): The N-terminal polybasic region of the normal prion protein, PrP(C), which encompasses residues 23-31, is important for prion pathogenesis by affecting conversion of PrP(C) into the pathogenic isoform, PrP(Sc). We previously reported transgenic mice expressing PrP with residues 25-50 deleted in the PrP-null background, designated as Tg(PrPpreOR)/Prnp (0/0) mice. Here, we produced two new lines of Tg(PrPpreOR)/Prnp (0/0) mice, each expressing the mutant protein, PrPpreOR, 1.1 and 1.6 times more than PrP(C) in wild-type mice, and subsequently intracerebrally inoculated RML and 22L prions into them. The lower expresser showed slightly reduced susceptibility to RML prions but not to 22L prions. The higher expresser exhibited enhanced susceptibility to both prions. No prion transmission barrier was created in Tg(PrPpreOR)/Prnp (0/0) mice against full-length PrP(Sc). PrP(Sc)preOR accumulated in the brains of infected Tg(PrPpreOR)/Prnp (0/0) mice less than PrP(Sc) in control wild-type mice, although lower in RML-infected Tg(PrPpreOR)/Prnp (0/0) mice than in 22L-infected mice. Prion infectivity in infected Tg(PrPpreOR)/Prnp (0/0) mice was also lower than that in wild-type mice. These results indicate that deletion of residues 25-50 only slightly affects prion susceptibility, the conversion of PrP(C) into PrP(Sc), and prion infectivity in a strain-specific way. PrPpreOR retains residues 23-24 and lacks residues 25-31 in the polybasic region. It is thus conceivable that residues 23-24 rather than 25-31 are important for the polybasic region to support prion pathogenesis. However, other investigators have reported that residues 27-31 not 23-24 are important to support prion pathogenesis. Taken together, the polybasic region might support prion pathogenesis through multiple sites including residues 23-24 and 27-31.
(キーワード): Amino Acid Sequence / Animals / Disease Susceptibility / Mice / Mice, Inbred C57BL / Mice, Transgenic / Prion Diseases / Prion Proteins / Repetitive Sequences, Amino Acid / Sequence Deletion
(徳島大学機関リポジトリ): ● Metadata: 2003324
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s00705-017-3295-3
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28255815; ● Summary page in Scopus @ Elsevier: 2-s2.0-85014121673

(徳島大学機関リポジトリ: 2003324, DOI: 10.1007/s00705-017-3295-3, PubMed: 28255815, Elsevier: Scopus) Taichi Hamanaka, Keiko Nishizawa, Yuji Sakasegawa, Ayumi Oguma, Kenta Teruya, Hiroshi Kurahashi, Hideyuki Hara, Suehiro Sakaguchi and Katsumi Doh-ura :
Melanin or melanin-like substance interacts with the N-terminal portion of prion protein and inhibits abnormal prion protein formation in prion-infected cells.,
Journal of Virology, 91, 6, e01862-16, 2017.

(要約): 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. The chemical nature of these components was consistent with that of melanin. In fact, synthetic melanin produced from tyrosine or 3-hydroxy-l-tyrosine inhibited abnormal PrP formation. Melanin did not modify cellular or cell surface PrP levels, nor did it modify lipid raft or cellular cholesterol levels. Neither did it enhance autophagy or lysosomal function. Melanin was capable of interacting with PrP at two N-terminal domains. Specifically, it strongly interacted with the PrP region of amino acids 23 to 50 including a positively charged amino acid cluster and weakly interacted with the PrP octarepeat peptide region of residues 51 to 90. However, the in vitro and in vivo data were inconsistent with those of prion-infected cells. Abnormal PrP formation in protein misfolding cyclic amplification was not inhibited by melanin. Survival after prion infection was not significantly altered in albino mice or exogenously melanin-injected mice compared with that of control mice. These data suggest that melanin, a main determinant of skin color, is not likely to modify prion disease pathogenesis, even though racial differences in the incidence of human prion diseases have been reported. Thus, the findings identify an interaction between melanin and the N terminus of PrP, but the pathophysiological roles of the PrP-melanin interaction remain unclear.IMPORTANCE The N-terminal region of PrP is reportedly important for neuroprotection, neurotoxicity, and abnormal PrP formation, as this region is bound by many factors, such as metal ions, lipids, nucleic acids, antiprion compounds, and several proteins, including abnormal PrP in prion disease and the Aβ oligomer in Alzheimer's disease. In the present study, melanin, a main determinant of skin color, was newly found to interact with this N-terminal region and inhibits abnormal PrP formation in prion-infected cells. However, the data for prion infection in mice lacking melanin production suggest that melanin is not associated with the prion disease mechanism, although the incidence of prion disease is reportedly much higher in white people than in black people. Thus, the roles of the PrP-melanin interaction remain to be further elucidated, but melanin might be a useful competitive tool for evaluating the functions of other ligands at the N-terminal region.
(キーワード): Animals / Cell Line / Melanins / Mice / Neurons / Prion Diseases / Prions / Protein Binding / Protein Interaction Mapping / Survival Analysis
(出版サイトへのリンク): ● Publication site (DOI): 10.1128/JVI.01862-16
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28077650; ● Search Scopus @ Elsevier (PMID): 28077650; ● Search Scopus @ Elsevier (DOI): 10.1128/JVI.01862-16

(DOI: 10.1128/JVI.01862-16, PubMed: 28077650) Keiji Uchiyama, Miyata Hironori, Masashi Yano, Yoshitaka Yamaguti, Imamura Morikazu, Muramatsu Naomi, Das Rani Nandita, Junji Chida, Hideyuki Hara and Suehiro Sakaguchi :
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.,
PLoS ONE, 9, 10, e109737, 2014.

(要約): 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(MHM223-88)/Prnp 0/0 mice, neither developed the disease nor accumulated MHM2Sc23-88 in their brains after inoculation with RML prions. In contrast, RML-inoculated Tg(MHM223-88)/Prnp 0/+ mice developed the disease with abundant accumulation of MHM2Sc23-88 in their brains. These results indicate that MHM223-88 itself might either lose or greatly reduce the converting capacity to MHM2Sc23-88, and that the co-expressing wild-type PrPC can stimulate the conversion of MHM223-88 to MHM2Sc23-88 in trans. In the present study, we confirmed that Tg(MHM223-88)/Prnp 0/0 mice remained resistant to RML prions for up to 730 days after inoculation. However, we found that Tg(MHM223-88)/Prnp 0/0 mice were susceptible to 22L prions, developing the disease with prolonged incubation times and accumulating MHM2Sc23-88 in their brains. We also found accelerated conversion of MHM223-88 into MHM2Sc23-88 in the brains of RML- and 22L-inoculated Tg(MHM223-88)/Prnp 0/+ mice. However, wild-type PrPSc accumulated less in the brains of these inoculated Tg(MHM223-88)/Prnp 0/+ mice, compared with RML- and 22L-inoculated Prnp 0/+ mice. These results show that MHM223-88 itself can convert into MHM2Sc23-88 without the help of the trans-acting PrPC, and that, irrespective of prion strains inoculated, the co-expressing wild-type PrPC stimulates the conversion of MHM223-88 into MHM2Sc23-88, but to the contrary, the co-expressing MHM223-88 disturbs the conversion of wild-type PrPC into PrPSc.
(徳島大学機関リポジトリ): ● Metadata: 2000097
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.pone.0109737
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25330286; ● Search Scopus @ Elsevier (PMID): 25330286; ● Search Scopus @ Elsevier (DOI): 10.1371/journal.pone.0109737

(徳島大学機関リポジトリ: 2000097, DOI: 10.1371/journal.pone.0109737, PubMed: 25330286) Ken'ichi Hagiwara, Hideyuki Hara and Kentaro Hanada :
Species-barrier phenomenon in prion transmissibility from a viewpoint of protein science,
The Journal of Biochemistry, 153, 2, 139-145, 2013.

(要約): Transmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal infectious neurodegenerative disorders. Their causative agents are prions, which are composed of disease-associated forms of prion protein (PrP(Sc)). Naturally occurring cases of TSEs are found in several mammalian species including humans, sheep, goats, minks, cattle and deer. Prions are also experimentally transmissible to other mammals such as mice, hamsters and monkeys, but interspecies transmission is often inefficient due to the 'species-barrier'. Studies have suggested that the barrier is not only simply determined by differences in amino acid sequences of cellular PrP (PrP(C)) among animal species, but also by prion strains which are closely associated with conformational properties of PrP(Sc) aggregates. Although the conformational properties of PrP(Sc) remain largely unknown, recent investigation of local structures of PrP(C) and, in particular, structural modelling of PrP(Sc) aggregates have provided molecular insight into this field. In this review, we discuss the species-barrier phenomenon in terms of the protein science.
(キーワード): Amyloid / Animals / Cattle / Goats / Humans / Prion Diseases / Prions / Sheep / Spectrophotometry, Infrared
(出版サイトへのリンク): ● Publication site (DOI): 10.1093/jb/mvs148
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23284000; ● Search Scopus @ Elsevier (PMID): 23284000; ● Search Scopus @ Elsevier (DOI): 10.1093/jb/mvs148

(DOI: 10.1093/jb/mvs148, PubMed: 23284000) Hideyuki Hara, Yuko Okemoto-Nakamura, Fumiko Shinkai-Ouchi, Kentaro Hanada, Yoshio Yamakawa and Ken'ichi Hagiwara :
Mouse Prion Protein (PrP) Segment 100 to 104 Regulates Conversion of PrPC to PrPSc in Prion-Infected Neuroblastoma Cells,
Journal of Virology, 86, 10, 5626-5636, 2012.

(要約): Prion diseases are characterized by the replicative propagation of disease-associated forms of prion protein (PrP(Sc); PrP refers to prion protein). The propagation is believed to proceed via two steps; the initial binding of the normal form of PrP (PrP(C)) to PrP(Sc) and the subsequent conversion of PrP(C) to PrP(Sc). We have explored the two-step model in prion-infected mouse neuroblastoma (ScN2a) cells by focusing on the mouse PrP (MoPrP) segment 92-GGTHNQWNKPSKPKTN-107, which is within a region previously suggested to be part of the binding interface or shown to differ in its accessibility to anti-PrP antibodies between PrP(C) and PrP(Sc). Exchanging the MoPrP segment with the corresponding chicken PrP segment (106-GGSYHNQKPWKPPKTN-121) revealed the necessity of MoPrP residues 99 to 104 for the chimeras to achieve the PrP(Sc) state, while segment 95 to 98 was replaceable with the chicken sequence. An alanine substitution at position 100, 102, 103, or 104 of MoPrP gave rise to nonconvertible mutants that associated with MoPrP(Sc) and interfered with the conversion of endogenous MoPrP(C). The interference was not evoked by a chimera (designated MCM2) in which MoPrP segment 95 to 104 was changed to the chicken sequence, though MCM2 associated with MoPrP(Sc). Incubation of the cells with a synthetic peptide composed of MoPrP residues 93 to 107 or alanine-substituted cognates did not inhibit the conversion, whereas an anti-P8 antibody recognizing the above sequence in PrP(C) reduced the accumulation of PrP(Sc) after 10 days of incubation of the cells. These results suggest the segment 100 to 104 of MoPrP(C) plays a key role in conversion after binding to MoPrP(Sc).
(キーワード): Amino Acid Motifs / Amino Acid Sequence / Animals / Cell Line / Chickens / Humans / Mice / Molecular Sequence Data / Neuroblastoma / PrPC Proteins / PrPSc Proteins / Prion Diseases / Prions / Sequence Alignment
(出版サイトへのリンク): ● Publication site (DOI): 10.1128/JVI.06606-11
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22398286; ● Search Scopus @ Elsevier (PMID): 22398286; ● Search Scopus @ Elsevier (DOI): 10.1128/JVI.06606-11

(DOI: 10.1128/JVI.06606-11, PubMed: 22398286)

MISC

研究者総覧に該当データはありませんでした。

総説・解説

原英之 :
ウイルス感染を用いたプリオン病発症モデルの構築,
ブレインサイエンス・レビュー2021, 195-212, 2021年4月. 原英之 :
「プリオン仮説」の最終証明に挑戦しませんか?,
生物工学会誌, 91, 8, 471, 2013年8月.

(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1540854195288834944; ● Summary page in Scopus @ Elsevier: 2-s2.0-84896086245

(CiNii: 1540854195288834944, Elsevier: Scopus)

講演・発表

Hagiwara Ken'ichi, Sato Yuko, Yamakawa Yoshio, Hideyuki Hara, Shibata Hiroaki and Ono Fumiko :
Interspecies transmission of atypical L-BSE prion to non-human primates(cynomolgus macaques) alleviates PrPSc glycoform profile of cattle L-BSE trait, but preserves incompetent transmissibility to inbred mice,
PRION 2016, May 2016.

(キーワード): プリオン / L-BSE / PrPSc

Hideyuki Hara, Yuko Okemoto-Nakamura, Fumiko Shinkai-Ouchi, Kentaro Hanada, Yoshio Yamakawa and Ken'ichi Hagiwara :
Mouse prion protein (PrP) segment 100 to 104 regulates conversion of PrPC to PrPSc in prion-infected neuroblastoma cells,
Asian Pacific Prion Symposium 2012, Jul. 2012. 原英之, 千田淳司, 坂口末廣 :
ネクロトーシスをトリガーとした異常型プリオン蛋白質産生の分子機構,
第45回日本分子生物学会年会, 2022年11月. 原英之, 千田淳司, 坂口末廣 :
インフルエンザウイルス感染は神経細胞において感染性プリオンの産生を引き起こす,
第44回日本分子生物学会年会, 2021年12月. 千田淳司, 原英之, 坂口末廣 :
プリオン蛋白質はインフルエンザ A ウイルス感染による重症化を軽減する,
第42回日本分子生物学会年会, 2019年12月. 原英之, 千田淳司, 坂口末廣 :
ウイルス感染を用いたプリオン病発症機構の解明,
第42回日本分子生物学会年会, 2019年12月. 原英之, 千田淳司, 坂口末廣 :
インフルエンザウイルス感染は神経細胞において異常型プリオン産生のトリガーとなる,
第41回日本分子生物学会年会, 2018年11月. 千田淳司, 原英之, 坂口末廣 :
プリオン蛋白質はインフルエンザAウイルス感染に防御的に機能する,
第66回日本ウイルス学会学術集会, 2018年10月. 千田淳司, 原英之, 坂口末廣 :
Prion protein protects mice from lethal infection with Influenza A virues,
2017年度生命科学系学会合同年次大会 (ConBio2017) 第 40回日本分子生物学会年会/第90回日本生化学会大会, 2017年12月. 原英之, 千田淳司, 坂口末廣 :
蛋白質凝集体「プリオン」による抗インフルエンザウイルス活性機構,
2017年度生命科学系学会合同年次大会 (ConBio2017) 第 40回日本分子生物学会年会/第90回日本生化学会大会, 2017年12月. 原英之, 千田淳司, 坂口末廣 :
蛋白質凝集体「プリオン」による抗インフルエンザウイルス活性機構の解明,
第39回日本分子生物学会年会, 2016年12月. 原英之, 千田淳司, 坂口末廣 :
蛋白質凝集体「プリオン」による抗インフルエンザ活性の発見,
第38回日本分子生物学会年会第88回日本生化学会大会合同大会, 2015年12月. 清水七海, 古賀雄一, 作道章一, 原英之, 坂口末廣, 金谷茂則 :
超好熱菌由来プロテアーゼによるプリオンタンパク質分解の評価,
第87回日本生化学会, 2014年10月. 古賀雄一, 清水七海, 作道章一, 原英之, 坂口末廣, 金谷茂則 :
超好熱菌由来プロテアーゼによるプリオンタンパク質分解の評価,
第66回日本生物工学会大会, 2014年9月.

研究会・報告書: 千田淳司, 原英之, 坂口末廣 :
肺で発現する正常プリオン蛋白質の機能解析,
第32回中国四国ウイルス研究会, 2017年6月.

特許: 研究者総覧に該当データはありませんでした。
作品: 研究者総覧に該当データはありませんでした。
補助金・競争的資金: ネクロトーシスに着目したプリオン病の病態解明と治療法創出 (研究課題/領域番号: 24K10661 )
プリオン病の予防・治療法開発を目指したプリオン以外の病原体の究明と病態解明研究 (研究課題/領域番号: 23K27489 )
ネクロトーシスをトリガーとした異常型プリオン蛋白質産生メカニズムの解明 (研究課題/領域番号: 21K07462 )
プリオン病の神経細胞障害のメカニズム解明とその障害を改善する化合物の探索 (研究課題/領域番号: 19H03548 )
培養細胞を用いた世界初のプリオン病モデル構築と異常型プリオン産生メカニズムの解明 (研究課題/領域番号: 18K07499 )
プリオン蛋白質は耐性ウイルスを誘導しない夢のインフルエンザ薬のターゲットである (研究課題/領域番号: 17K19661 )
プリオン病の新規病態として発見した細胞膜蛋白質の小胞輸送障害のメカニズム解明 (研究課題/領域番号: 26293212 )
正常プリオン蛋白質の銅イオン結合部位を介したプリオン病原性の決定メカニズムの解明 (研究課題/領域番号: 25870479 )
プリオン感染に必須なプリオン蛋白質以外の分子の同定 (研究課題/領域番号: 25670422 )
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専門分野・研究分野: 研究者総覧に該当データはありませんでした。
所属学会・所属協会: 日本分子生物学会
Asian Pacific Society of Prion Research
委員歴・役員歴: Asian Pacific Society of Prion Research (Councilor)
受賞: 2012年7月, Best Poster Prize (Asian Pacific Prion Symposium 2012)
2012年7月, ZENSHO Prize (Asian Pacific Prion Symposium 2012)
2016年12月, 優秀ポスター賞 (第39回日本分子生物学会年会)
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Jグローバル最終確認日: 2025/8/23 01:36
氏名（漢字）: 原英之
氏名（フリガナ）: ハラヒデユキ
氏名（英字）: Hara Hideyuki
所属機関: 大阪大学特任准教授(常勤)

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researchmap最終確認日: 2025/8/24 02:34
氏名（漢字）: 原英之
氏名（フリガナ）: ハラヒデユキ
氏名（英字）: Hara Hideyuki
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所属: 大阪大学
部署: 感染症総合教育研究拠点
職名: 特任准教授（常勤）
学位: 博士（医学）
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研究者番号: 40469953

所属（現在）: 2025/4/1 : 大阪大学, 感染症総合教育研究拠点, 特任准教授(常勤)

所属（過去の研究課題 情報に基づく）*注記: 2023/4/1 – 2024/4/1 : 大阪大学, 感染症総合教育研究拠点, 特任准教授(常勤)
2023/4/1 : 大阪大学, 感染症総合教育研究拠点, 特任准教授
2021/4/1 – 2022/4/1 : 徳島大学, 先端酵素学研究所, 助教
2017/4/1 – 2020/4/1 : 徳島大学, 先端酵素学研究所(次世代), 助教
2016/4/1 : 徳島大学, 先端酵素学研究所, 助教
2014/4/1 – 2016/4/1 : 徳島大学, 疾患酵素学研究センター, 助教
2013/4/1 : 徳島大学, 疾患酵素学研究センター, 特任助教

審査区分/研究分野

研究代表者

生物系 / 医歯薬学 / 内科系臨床医学 / 神経内科学 / 生物系 / 農学 / 動物生命科学 / 獣医学
小区分52020:神経内科学関連

研究代表者以外

生物系 / 医歯薬学 / 内科系臨床医学 / 神経内科学
内科学一般およびその関連分野
小区分51030:病態神経科学関連

キーワード

研究代表者

プリオン / 構造変換 / 銅イオン / オクタペプチドリピート / OR / リピート部位 / 銅 / 神経変性 / クロイツフェルト・ヤコブ病 / 狂牛病 / スクレイピー / プリオン病 / ウイルス / ウイルス感染 / 異常型 / ネクロトーシス

研究代表者以外

プリオン / ソーチリン / プリオン病 / プリオンタンパク質 / 感受性 / 構造変換 / 受容体 / 神経変性 / クロイツフェルト・ヤコブ病 / 狂牛病 / 蛋白質輸送 / 蛋白質分解 / ノックアウトマウス / 神経変性疾患 / プリオン蛋白質 / トランスジェニックマウス / アトラクチン / インスリン受容体 / ポストゴルジ小胞輸送 / 小胞輸送 / 細胞膜蛋白質 / Tgマウス / ポストゴルジ輸送 / インフルエンザ / インフルエンザウイルス / 抗体 / スーパーオキサイドジスムターゼ / Src / 活性酸素種 / 銅イオン / Srcファミリーキナーゼ / マクロファージ / A型インフルエンザウイルス / 銅 / スーパーオキシドジスムターゼ / エタノールアミン / 神経細胞死

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