A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration
Identifieur interne : 000487 ( Main/Exploration ); précédent : 000486; suivant : 000488A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration
Auteurs : Kanae Iijima-Ando [États-Unis] ; Lijuan Zhao ; Anthony Gatt ; Christopher Shenton ; Koichi Iijima [États-Unis]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-05-15.
Abstract
Hyperphosphorylation of the microtubule associated protein tau is detected in the brains of individuals with a range of neurodegenerative diseases including Alzheimer's disease (AD). An imbalance in phosphorylation and/or dephosphorylation of tau at disease-related sites has been suggested to initiate the abnormal metabolism and toxicity of tau in disease pathogenesis. However, the mechanisms underlying abnormal phosphorylation of tau in AD are not fully understood. Here, we show that the DNA damage-activated Checkpoint kinase 2 (Chk2) is a novel tau kinase and enhances tau toxicity in a transgenic Drosophila model. Overexpression of Drosophila Chk2 increases tau phosphorylation at Ser262 and enhances tau-induced neurodegeneration in transgenic flies expressing human tau. The non-phosphorylatable Ser262Ala mutation abolishes Chk2-induced enhancement of tau toxicity, suggesting that the Ser262 phosphorylation site is involved in the enhancement of tau toxicity by Chk2. In vitro kinase assays revealed that human Chk2 and a closely related checkpoint kinase 1 (Chk1) directly phosphorylate human tau at Ser262. We also demonstrate that Drosophila Chk2 does not modulate the activity of the fly homolog of microtubule affinity regulating kinase, which has been shown to be a physiological tau Ser262 kinase. Since accumulation of DNA damage has been detected in the brains of AD patients, our results suggest that the DNA damage-activated kinases Chk1 and Chk2 may be involved in tau phosphorylation and toxicity in the pathogenesis of AD.
Url:
DOI: 10.1093/hmg/ddq068
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration</title>
<author><name sortKey="Iijima Ando, Kanae" sort="Iijima Ando, Kanae" uniqKey="Iijima Ando K" first="Kanae" last="Iijima-Ando">Kanae Iijima-Ando</name>
</author>
<author><name sortKey="Zhao, Lijuan" sort="Zhao, Lijuan" uniqKey="Zhao L" first="Lijuan" last="Zhao">Lijuan Zhao</name>
</author>
<author><name sortKey="Gatt, Anthony" sort="Gatt, Anthony" uniqKey="Gatt A" first="Anthony" last="Gatt">Anthony Gatt</name>
</author>
<author><name sortKey="Shenton, Christopher" sort="Shenton, Christopher" uniqKey="Shenton C" first="Christopher" last="Shenton">Christopher Shenton</name>
</author>
<author><name sortKey="Iijima, Koichi" sort="Iijima, Koichi" uniqKey="Iijima K" first="Koichi" last="Iijima">Koichi Iijima</name>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">ISTEX</idno>
<idno type="RBID">ISTEX:786CC99C2BCE1446CE4C2F9F56046D55215F7933</idno>
<date when="2010" year="2010">2010</date>
<idno type="doi">10.1093/hmg/ddq068</idno>
<idno type="url">https://api.istex.fr/document/786CC99C2BCE1446CE4C2F9F56046D55215F7933/fulltext/pdf</idno>
<idno type="wicri:Area/Main/Corpus">002950</idno>
<idno type="wicri:Area/Main/Curation">002599</idno>
<idno type="wicri:Area/Main/Exploration">000487</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title level="a">A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration</title>
<author><name sortKey="Iijima Ando, Kanae" sort="Iijima Ando, Kanae" uniqKey="Iijima Ando K" first="Kanae" last="Iijima-Ando">Kanae Iijima-Ando</name>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Zhao, Lijuan" sort="Zhao, Lijuan" uniqKey="Zhao L" first="Lijuan" last="Zhao">Lijuan Zhao</name>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Gatt, Anthony" sort="Gatt, Anthony" uniqKey="Gatt A" first="Anthony" last="Gatt">Anthony Gatt</name>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Shenton, Christopher" sort="Shenton, Christopher" uniqKey="Shenton C" first="Christopher" last="Shenton">Christopher Shenton</name>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Iijima, Koichi" sort="Iijima, Koichi" uniqKey="Iijima K" first="Koichi" last="Iijima">Koichi Iijima</name>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation><wicri:noCountry code="syntax">???</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country>
</affiliation>
</author>
</analytic>
<monogr></monogr>
<series><title level="j">Human Molecular Genetics</title>
<idno type="ISSN">0964-6906</idno>
<idno type="eISSN">1460-2083</idno>
<imprint><publisher>Oxford University Press</publisher>
<date type="published" when="2010-05-15">2010-05-15</date>
<biblScope unit="volume">19</biblScope>
<biblScope unit="issue">10</biblScope>
<biblScope unit="page" from="1930">1930</biblScope>
<biblScope unit="page" to="1938">1938</biblScope>
</imprint>
<idno type="ISSN">0964-6906</idno>
</series>
<idno type="istex">786CC99C2BCE1446CE4C2F9F56046D55215F7933</idno>
<idno type="DOI">10.1093/hmg/ddq068</idno>
<idno type="ArticleID">ddq068</idno>
</biblStruct>
</sourceDesc>
<seriesStmt><idno type="ISSN">0964-6906</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass></textClass>
<langUsage><language ident="en">en</language>
</langUsage>
</profileDesc>
</teiHeader>
<front><div type="abstract">Hyperphosphorylation of the microtubule associated protein tau is detected in the brains of individuals with a range of neurodegenerative diseases including Alzheimer's disease (AD). An imbalance in phosphorylation and/or dephosphorylation of tau at disease-related sites has been suggested to initiate the abnormal metabolism and toxicity of tau in disease pathogenesis. However, the mechanisms underlying abnormal phosphorylation of tau in AD are not fully understood. Here, we show that the DNA damage-activated Checkpoint kinase 2 (Chk2) is a novel tau kinase and enhances tau toxicity in a transgenic Drosophila model. Overexpression of Drosophila Chk2 increases tau phosphorylation at Ser262 and enhances tau-induced neurodegeneration in transgenic flies expressing human tau. The non-phosphorylatable Ser262Ala mutation abolishes Chk2-induced enhancement of tau toxicity, suggesting that the Ser262 phosphorylation site is involved in the enhancement of tau toxicity by Chk2. In vitro kinase assays revealed that human Chk2 and a closely related checkpoint kinase 1 (Chk1) directly phosphorylate human tau at Ser262. We also demonstrate that Drosophila Chk2 does not modulate the activity of the fly homolog of microtubule affinity regulating kinase, which has been shown to be a physiological tau Ser262 kinase. Since accumulation of DNA damage has been detected in the brains of AD patients, our results suggest that the DNA damage-activated kinases Chk1 and Chk2 may be involved in tau phosphorylation and toxicity in the pathogenesis of AD.</div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
</list>
<tree><noCountry><name sortKey="Gatt, Anthony" sort="Gatt, Anthony" uniqKey="Gatt A" first="Anthony" last="Gatt">Anthony Gatt</name>
<name sortKey="Shenton, Christopher" sort="Shenton, Christopher" uniqKey="Shenton C" first="Christopher" last="Shenton">Christopher Shenton</name>
<name sortKey="Zhao, Lijuan" sort="Zhao, Lijuan" uniqKey="Zhao L" first="Lijuan" last="Zhao">Lijuan Zhao</name>
</noCountry>
<country name="États-Unis"><noRegion><name sortKey="Iijima Ando, Kanae" sort="Iijima Ando, Kanae" uniqKey="Iijima Ando K" first="Kanae" last="Iijima-Ando">Kanae Iijima-Ando</name>
</noRegion>
<name sortKey="Iijima, Koichi" sort="Iijima, Koichi" uniqKey="Iijima K" first="Koichi" last="Iijima">Koichi Iijima</name>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000487 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000487 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Sante |area= ParkinsonV1 |flux= Main |étape= Exploration |type= RBID |clé= ISTEX:786CC99C2BCE1446CE4C2F9F56046D55215F7933 |texte= A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration }}
This area was generated with Dilib version V0.6.23. |