8 results on '"Hara,Hideyuki"'
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2. Strain‐dependent role of copper in prion disease through binding to histidine residues in the N‐terminal domain of prion protein.
- Author
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Hara, Hideyuki, Miyata, Hironori, Chida, Junji, and Sakaguchi, Suehiro
- Subjects
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PRIONS , *PRION diseases , *N-terminal residues , *COPPER , *PROTEIN domains , *AMINO acid sequence - Abstract
The cellular prion protein, PrPC, is a copper‐binding protein abundantly expressed in the brain, particularly by neurons, and its conformational conversion into the amyloidogenic isoform, PrPSc, plays a key pathogenic role in prion diseases. However, the role of copper binding to PrPC 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/Prnp0/0 and TgPrP(5H > A)‐7524/Prnp0/0 mice, and similarly inoculated RML and BSE prions into them. Due to 2‐fold higher expression of PrP(5H > A) than PrPC in wild‐type (WT) mice, TgPrP(5H > A)‐7524/Prnp0/0 mice were highly susceptible to these prions, compared to WT mice. However, TgPrP(5H > A)‐7342/Prnp0/0 mice, which express PrP(5H > A) 1.2‐fold as high as PrPC 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 PrPSc created no prion transmission barrier to BSE prions. These results suggest that copper‐binding His residues in PrPC 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 PrPC. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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3. 中央アミノ酸残基はプリオン蛋白質PrPCが病原性アイソフォームに変換するのに重要である
- Author
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Pasiana, Agriani Dini, Miyata, Hironori, Chida, Junji, Hara, Hideyuki, Imamura, Morikazu, Atarashi, Ryuichiro, and Sakaguchi, Suehiro
- Subjects
prion ,neurodegenerative disease ,prion disease ,protein misfolding ,transgenic mice ,structure-function - Abstract
Conformational conversion of the cellular prion protein, PrPC, into the amyloidogenic isoform, PrPSc, is a key pathogenic event in prion diseases. However, the conversion mechanism remains to be elucidated. Here, we generated Tg(PrPΔ91-106)-8545/Prnp0/0 mice, which overexpress mouse PrP lacking residues 91-106. We showed that none of the mice became sick after intracerebral inoculation with RML, 22L, and FK-1 prion strains nor accumulated PrPScΔ91-106 in their brains except for a small amount of PrPScΔ91-106 detected in one 22L-inoculated mouse. However, they developed disease around 85 days after inoculation with bovine spongiform encephalopathy (BSE) prions with PrPScΔ91-106 in their brains. These results suggest that residues 91-106 are important for PrPC conversion into PrPSc in infection with RML, 22L, and FK-1 prions but not BSE prions. We then narrowed down the residues 91-106 by transducing various PrP deletional mutants into RML- and 22L-infected cells and identified that PrP mutants lacking residues 97-99 failed to convert into PrPSc in these cells. Our in vitro conversion assay also showed that RML, 22L, and FK-1 prions did not convert PrPΔ97-99 into PrPScΔ97-99, but BSE prions did. We further found that PrP mutants with proline residues at positions 97 to 99 or charged residues at positions 97 and 99 completely or almost completely lost their converting activity into PrPSc in RML- and 22L-infected cells. These results suggest that the structurally flexible and noncharged residues 97-99 could be important for PrPC conversion into PrPSc following infection with RML, 22L, and FK-1 prions but not BSE prions.
- Published
- 2022
4. Prion Protein Devoid of the Octapeptide Repeat Region Delays BSE Pathogenesis in Mice
- Author
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Hara, Hideyuki, Miyata, Hironori, Das, Nandita Rani, Chida, Junji, Yoshimochi, Tatenobu, Uchiyama, Keiji, Watanabe, Hitomi, Kondoh, Gen, Yokoyama, Takashi, and Sakaguchi, Suehiro
- Subjects
Octapeptide repeat ,Prion protein ,animal diseases ,Bovine spongiform encephalopathy (BSE) ,mental disorders ,Prion ,nervous system diseases ,Scrapie - Abstract
Conformational conversion of the cellular isoform of prion protein PrPC, into the abnormally folded, amyloidogenic isoform, PrPSc, 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 PrPC into PrPSc 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)/Prnp0/0 mice, did not reduced susceptibility to RML scrapie prions, with abundant accumulation of PrPScΔOR in their brains. We show here that Tg(PrPΔOR)/Prnp0/0 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 PrPScΔOR was markedly delayed in their brains. These results suggest that the OR region may have a crucial role in the conversion of PrPC into PrPSc after infection with BSE prions. However, Tg(PrPΔOR)/Prnp0/0 mice remained susceptible to RML and 22L scrapie prions, developing the disease without elongated incubation times after infection with RML and 22L prions. PrPScΔOR accumulated only slightly less in the brains of RML- or 22L-infected Tg(PrPΔOR)/Prnp0/0 mice than PrPSc in control wild-type mice. Taken together, these results indicate that the OR region of PrPC could play a differential role in the pathogenesis of BSE prions and RML or 22L scrapie prions. IMPORTANCE Structure-function relationship studies of PrPC conformational conversion into PrPSc are worthwhile to understand the mechanism of the conversion of PrPC into PrPSc. We show here that, by inoculating the three different prion strains of RML, 22L and BSE prions, into Tg(PrP∆OR)/Prnp0/0 mice, the OR region could play a differential role in the conversion of PrPC into PrPSc after infection with RML or 22L scrapie prions and BSE prions. PrPΔOR was efficiently converted into PrPScΔOR after infection with RML and 22L prions. However, the conversion of PrPΔOR into PrPScΔOR was markedly delayed after infection with BSE prions. Further investigation into the role of the OR region in the conversion of PrPC into PrPSc after infection with BSE prions might be helpful for understanding the pathogenesis of BSE prions.
- Published
- 2017
5. Species-barrier phenomenon in prion transmissibility from a viewpoint of protein science.
- Author
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Hagiwara, Ken’ichi, Hara, Hideyuki, and Hanada, Kentaro
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PRIONS , *CHRONIC wasting disease , *MOLECULAR structure , *MOLECULAR weights , *AMYLOID , *AMINO acid sequence - Abstract
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 (PrPSc). 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 (PrPC) among animal species, but also by prion strains which are closely associated with conformational properties of PrPSc aggregates. Although the conformational properties of PrPSc remain largely unknown, recent investigation of local structures of PrPC and, in particular, structural modelling of PrPSc aggregates have provided molecular insight into this field. In this review, we discuss the species-barrier phenomenon in terms of the protein science. [ABSTRACT FROM AUTHOR]
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- 2013
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6. An improved method for cell-to-cell transmission of infectious prion
- Author
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Tanaka, Masahiko, Hara, Hideyuki, Nishina, Hiroshi, Hanada, Kentaro, Hagiwara, Ken’ichi, and Maehama, Tomohiko
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PRIONS , *CELL culture , *PRION diseases , *PATHOLOGY , *CYTOLOGY , *BIOCHEMISTRY - Abstract
Abstract: Prion diseases are characterized by the accumulation of a pathological form of prion protein (PrPSc), which behaves as an infectious agent. Here we developed an in vitro co-culture system to analyze the PrPSc transmission from ScN2a cell, which persistently retains PrPSc, to naïve N2a cell. In this cell-to-cell transmission system, PrPSc transmitted to recipient N2a cell was able to be detected within 5–7days. Further characterization showed that higher cell density greatly facilitated the transmission of PrPSc. This improved in vitro transmission method may become a useful tool for unveiling the molecular mechanism of PrPSc transmission. [Copyright &y& Elsevier]
- Published
- 2010
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7. Virus Infection, Genetic Mutations, and Prion Infection in Prion Protein Conversion.
- Author
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Hara, Hideyuki and Sakaguchi, Suehiro
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VIRUS diseases , *GENETIC mutation , *PRION diseases , *GENETIC disorders , *INFLUENZA A virus , *PRIONS - Abstract
Conformational conversion of the cellular isoform of prion protein, PrPC, into the abnormally folded, amyloidogenic isoform, PrPSc, is an underlying pathogenic mechanism in prion diseases. The diseases manifest as sporadic, hereditary, and acquired disorders. Etiological mechanisms driving the conversion of PrPC into PrPSc are unknown in sporadic prion diseases, while prion infection and specific mutations in the PrP gene are known to cause the conversion of PrPC into PrPSc in acquired and hereditary prion diseases, respectively. We recently reported that a neurotropic strain of influenza A virus (IAV) induced the conversion of PrPC into PrPSc as well as formation of infectious prions in mouse neuroblastoma cells after infection, suggesting the causative role of the neuronal infection of IAV in sporadic prion diseases. Here, we discuss the conversion mechanism of PrPC into PrPSc in different types of prion diseases, by presenting our findings of the IAV infection-induced conversion of PrPC into PrPSc and by reviewing the so far reported transgenic animal models of hereditary prion diseases and the reverse genetic studies, which have revealed the structure-function relationship for PrPC to convert into PrPSc after prion infection. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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8. N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases.
- Author
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Hara, Hideyuki and Sakaguchi, Suehiro
- Subjects
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PRION diseases , *BOVINE spongiform encephalopathy , *PRIONS , *CREUTZFELDT-Jakob disease , *PROTEINS - Abstract
The normal cellular isoform of prion protein, designated PrPC, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrPSc, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrPC is a membrane glycoprotein consisting of the non-structural N-terminal domain and the globular C-terminal domain. During conversion of PrPC to PrPSc, 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 PrPSc. Reverse genetic studies using reconstituted PrPC-knockout mice with various mutant PrP molecules have revealed that the N-terminal domain has an important role in the normal function of PrPC and the conversion of PrPC to PrPSc. 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 PrPC, the conversion of PrPC to PrPSc, and the neurotoxicity of PrPSc by focusing on the roles of the N-terminal regions in these topics. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
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