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ID 117617
Title Alternative
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
Author
Pasiana, Agriani Dini Tokushima University
Miyata, Hironori University of Occupational and Environmental Health
Imamura, Morikazu University of Miyazaki
Atarashi, Ryuichiro University of Miyazaki
Keywords
prion
prion disease
protein misfolding
structure-function
transgenic mice
neurodegenerative disease
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Journal of Biological Chemistry
ISSN
00219258
NCID
AA1202441X
Publisher
American Society for Biochemistry and Molecular Biology|Elsevier
Volume
298
Issue
9
Start Page
102381
Published Date
2022-08-13
Remark
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。
Rights
This is an open access article under the CCBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3662号
Diploma Number
甲医第1544号
Granted Date
2022-09-22
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Institute of Advanced Medical Sciences