ID | 114612 |
著者 |
Yamashita, Arisa
Tokushima University
Shiro, Yuki
Tokushima University
Hiraki, Yuri
Tokushima University
Yujiri, Takatoshi
Tokushima University
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キーワード | CLN6
NCL
ER
Kufs
|
資料タイプ |
学術雑誌論文
|
抄録 | CLN6, spanning the endoplasmic reticulum transmembrane, is a protein of unknown function. Mutations in the CLN6 gene are linked to an autosomal recessively inherited disorder termed CLN6 disease, classified as a form of the neuronal ceroid lipofuscinoses (NCL). The pathogenesis of CLN6 disease remains poorly understood due to a lack of information about physiological roles CLN6 plays. We previously demonstrated that CLN6 has the ability to prevent protein aggregate formation, and thus hypothesized that the abrogation of CLN6’s anti-aggregate activity underlies the development of CLN6 disease. To test this hypothesis, we narrowed down the region vital for CLN6’s anti-aggregate activity, and subsequently investigated if pathogenic mutations within the region attenuate CLN6’s anti-aggregate activity toward four aggregation-prone αB-crystallin (αBC) mutants. None of the four αBC mutants was prevented from aggregating by the Arg106ProfsX truncated CLN6 mutant, the human counterpart of the nclf mutant identified in a naturally occurring mouse model of late infantile-onset CLN6 disease. In contrast, the Arg149Cys and the Arg149His CLN6 mutants, both associated with adult-onset CLN6 disease, blocked aggregation of two out of and all of the four αBC mutants, respectively, indicating that CLN6’s anti-aggregate activity is differentially modulated according to the substitution pattern at the same amino acid position. Collectively, we here propose that the graded reduction in CLN6’s anti-aggregate activity governs the clinical course of late infantile- and adult- onset NCL.
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掲載誌名 |
Biochemical and Biophysical Research Communications
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ISSN | 0006291X
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cat書誌ID | AA00564395
AA11542044
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出版者 | Elsevier
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巻 | 525
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号 | 4
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開始ページ | 883
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終了ページ | 888
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発行日 | 2020-03-11
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権利情報 | © 2020. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
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EDB ID | |
出版社版DOI | |
出版社版URL | |
フルテキストファイル | |
言語 |
eng
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著者版フラグ |
著者版
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部局 |
薬学系
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