Haiyan Xia, Yun Cao, Xiaoman Dai, Zvonimir Marelja, Di Zhou, Ran Mo, Sahar Al-Mahdawi, Mark A. Pook, Silke Leimkühler, Tracey A. Rouault, Kuanyu Li
- Friedreich ataxia (FRDA) is an inherited neurodegenerative disease caused by frataxin (FXN) deficiency. The nervous system and heart are the most severely affected tissues. However, highly mitochondria-dependent tissues, such as kidney and liver, are not obviously affected, although the abundance of FXN is normally high in these tissues. In this study we have revealed two novel FXN isoforms (II and III), which are specifically expressed in affected cerebellum and heart tissues, respectively, and are functional in vitro and in vivo. Increasing the abundance of the heart-specific isoform III significantly increased the mitochondrial aconitase activity, while over-expression of the cerebellum-specific isoform II protected against oxidative damage of Fe-S cluster-containing aconitase. Further, we observed that the protein level of isoform III decreased in FRDA patient heart, while the mRNA level of isoform II decreased more in FRDA patient cerebellum compared to total FXN mRNA. Our novel findings are highly relevant to understanding theFriedreich ataxia (FRDA) is an inherited neurodegenerative disease caused by frataxin (FXN) deficiency. The nervous system and heart are the most severely affected tissues. However, highly mitochondria-dependent tissues, such as kidney and liver, are not obviously affected, although the abundance of FXN is normally high in these tissues. In this study we have revealed two novel FXN isoforms (II and III), which are specifically expressed in affected cerebellum and heart tissues, respectively, and are functional in vitro and in vivo. Increasing the abundance of the heart-specific isoform III significantly increased the mitochondrial aconitase activity, while over-expression of the cerebellum-specific isoform II protected against oxidative damage of Fe-S cluster-containing aconitase. Further, we observed that the protein level of isoform III decreased in FRDA patient heart, while the mRNA level of isoform II decreased more in FRDA patient cerebellum compared to total FXN mRNA. Our novel findings are highly relevant to understanding the mechanism of tissue-specific pathology in FRDA.…
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MetadatenVerfasserangaben: | Haiyan Xia, Yun Cao, Xiaoman Dai, Zvonimir Marelja, Di Zhou, Ran Mo, Sahar Al-Mahdawi, Mark A. Pook, Silke LeimkühlerORCiDGND, Tracey A. Rouault, Kuanyu Li |
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DOI: | https://doi.org/10.1371/journal.pone.0047847 |
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ISSN: | 1932-6203 |
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Titel des übergeordneten Werks (Englisch): | PLOS ONE |
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Verlag: | PUBLIC LIBRARY SCIENCE |
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Verlagsort: | SAN FRANCISCO |
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Publikationstyp: | Wissenschaftlicher Artikel |
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Sprache: | Englisch |
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Jahr der Erstveröffentlichung: | 2012 |
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Erscheinungsjahr: | 2012 |
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Datum der Freischaltung: | 26.03.2017 |
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Band: | 7 |
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Ausgabe: | 10 |
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Seitenanzahl: | 11 |
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Fördernde Institution: | National Institute of Child Health and Human Development, National
Institutes of Health; Friedreich ataxia research association; National
Nature Science Foundation of China (NSFC) [31071085]; Scientific
Research Foundation for the Returned Overseas Chinese Scholars, State
Education Ministry; State Key Laboratory of Pharmaceutical Biotechnology
[ZZYJ-SN-201006]; Studienstiftung des Deutschen Volkes; Deutscher
Akademischer Austauschdienst scholarship; Deutsche
Forschungsgemeinschaft [SL1171/5-3] |
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