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タイトル別表記
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
Central residues crucial for prion protein conversion
著者
パシアナ, アグリアニ ディニ 徳島大学大学院医学研究科(医学専攻)
Miyata, Hironori University of Occupational and Environmental Health
Imamura, Morikazu University of Miyazaki
Atarashi, Ryuichiro University of Miyazaki
キーワード
prion
prion disease
protein misfolding
structure-function
transgenic mice
neurodegenerative disease
資料タイプ
学位論文
抄録
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.
掲載誌名
Journal of Biological Chemistry
ISSN
00219258
cat書誌ID
AA1202441X
出版者
American Society for Biochemistry and Molecular Biology|Elsevier
298
9
開始ページ
102381
発行日
2022-08-13
備考
内容要旨・審査要旨・論文本文の公開
本論文は,著者Agriani Dini Pasianaの学位論文として提出され,学位審査・授与の対象となっている。
権利情報
This is an open access article under the CCBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3662号
学位記番号
甲医第1544号
学位授与年月日
2022-09-22
学位名
博士(医学)
学位授与機関
徳島大学
部局
先端酵素学研究所