Overexpression of 14-3-3ζ Promotes Tau Phosphorylation at Ser262 and Accelerates Proteosomal Degradation of Synaptophysin in Rat Primary Hippocampal Neurons
Identifieur interne : 000734 ( Pmc/Checkpoint ); précédent : 000733; suivant : 000735Overexpression of 14-3-3ζ Promotes Tau Phosphorylation at Ser262 and Accelerates Proteosomal Degradation of Synaptophysin in Rat Primary Hippocampal Neurons
Auteurs : Hamid Y. Qureshi [Canada] ; Dong Han [Canada] ; Ryen Macdonald [Canada] ; Hemant K. Paudel [Canada]Source :
- PLoS ONE [ 1932-6203 ] ; 2013.
Abstract
β-amyloid peptide accumulation, tau hyperphosphorylation, and synapse loss are characteristic neuropathological symptoms of Alzheimer’s disease (AD). Tau hyperphosphorylation is suggested to inhibit the association of tau with microtubules, making microtubules unstable and causing neurodegeneration. The mechanism of tau phosphorylation in AD brain, therefore, is of considerable significance. Although PHF-tau is phosphorylated at over 40 Ser/Thr sites, Ser262 phosphorylation was shown to mediate β-amyloid neurotoxicity and formation of toxic tau lesions in the brain.
Url:
DOI: 10.1371/journal.pone.0084615
PubMed: 24367683
PubMed Central: 3868614
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"> Overexpression of 14-3-3ζ Promotes Tau Phosphorylation at Ser<sup>262</sup> and Accelerates Proteosomal Degradation of Synaptophysin in Rat Primary Hippocampal Neurons</title><author><name sortKey="Qureshi, Hamid Y" sort="Qureshi, Hamid Y" uniqKey="Qureshi H" first="Hamid Y." last="Qureshi">Hamid Y. Qureshi</name><affiliation wicri:level="1"><nlm:aff id="aff1"> The<addr-line>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Han, Dong" sort="Han, Dong" uniqKey="Han D" first="Dong" last="Han">Dong Han</name><affiliation wicri:level="1"><nlm:aff id="aff1"> The<addr-line>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Macdonald, Ryen" sort="Macdonald, Ryen" uniqKey="Macdonald R" first="Ryen" last="Macdonald">Ryen Macdonald</name><affiliation wicri:level="1"><nlm:aff id="aff1"> The<addr-line>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Paudel, Hemant K" sort="Paudel, Hemant K" uniqKey="Paudel H" first="Hemant K." last="Paudel">Hemant K. Paudel</name><affiliation wicri:level="1"><nlm:aff id="aff1"> The<addr-line>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24367683</idno><idno type="pmc">3868614</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868614</idno><idno type="RBID">PMC:3868614</idno><idno type="doi">10.1371/journal.pone.0084615</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000B04</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B04</idno><idno type="wicri:Area/Pmc/Curation">000B04</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000B04</idno><idno type="wicri:Area/Pmc/Checkpoint">000734</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000734</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"> Overexpression of 14-3-3ζ Promotes Tau Phosphorylation at Ser<sup>262</sup> and Accelerates Proteosomal Degradation of Synaptophysin in Rat Primary Hippocampal Neurons</title><author><name sortKey="Qureshi, Hamid Y" sort="Qureshi, Hamid Y" uniqKey="Qureshi H" first="Hamid Y." last="Qureshi">Hamid Y. Qureshi</name><affiliation wicri:level="1"><nlm:aff id="aff1"> The<addr-line>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Han, Dong" sort="Han, Dong" uniqKey="Han D" first="Dong" last="Han">Dong Han</name><affiliation wicri:level="1"><nlm:aff id="aff1"> The<addr-line>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Macdonald, Ryen" sort="Macdonald, Ryen" uniqKey="Macdonald R" first="Ryen" last="Macdonald">Ryen Macdonald</name><affiliation wicri:level="1"><nlm:aff id="aff1"> The<addr-line>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Paudel, Hemant K" sort="Paudel, Hemant K" uniqKey="Paudel H" first="Hemant K." last="Paudel">Hemant K. Paudel</name><affiliation wicri:level="1"><nlm:aff id="aff1"> The<addr-line>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>β-amyloid peptide accumulation, tau hyperphosphorylation, and synapse loss are characteristic neuropathological symptoms of Alzheimer’s disease (AD). Tau hyperphosphorylation is suggested to inhibit the association of tau with microtubules, making microtubules unstable and causing neurodegeneration. The mechanism of tau phosphorylation in AD brain, therefore, is of considerable significance. Although PHF-tau is phosphorylated at over 40 Ser/Thr sites, Ser<sup>262</sup> phosphorylation was shown to mediate β-amyloid neurotoxicity and formation of toxic tau lesions in the brain. <italic>In vitro</italic>, PKA is one of the kinases that phosphorylates <named-content content-type="gene">tau at</named-content> Ser<sup>262</sup>, but the mechanism by which it phosphorylates tau in AD brain is not very clear. 14-3-3ζ is associated with neurofibrillary tangles and is upregulated in AD brain. In this study, we show that 14-3-3ζ promotes tau phosphorylation at Ser<sup>262</sup> by PKA in differentiating neurons. When overexpressed in rat hippocampal primary neurons, 14-3-3ζ causes an increase in Ser<sup>262</sup> phosphorylation, a decrease in the amount of microtubule-bound tau, a reduction in the amount of polymerized microtubules, as well as microtubule instability. More importantly, the level of pre-synaptic protein synaptophysin was significantly reduced. Downregulation of synaptophysin in 14-3-3ζ overexpressing neurons was mitigated by inhibiting the proteosome, indicating that 14-3-3ζ promotes proteosomal degradation of synaptophysin. When 14-3-3ζ overexpressing neurons were treated with the microtubule stabilizing drug taxol, tau Ser<sup>262</sup> phosphorylation decreased and synaptophysin level was restored. Our data demonstrate that overexpression of 14-3-3ζ accelerates proteosomal turnover of synaptophysin by promoting the destabilization of microtubules. Synaptophysin is involved in synapse formation and neurotransmitter release. Our results suggest that 14-3-3ζ may cause synaptic pathology by reducing synaptophysin levels in the brains of patients suffering from AD. </p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lee, Vm" uniqKey="Lee V">VM Lee</name></author><author><name sortKey="Goedert, M" uniqKey="Goedert M">M Goedert</name></author><author><name sortKey="Trojanowski, Jq" uniqKey="Trojanowski J">JQ Trojanowski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, G" uniqKey="Lee G">G Lee</name></author><author><name sortKey="Leugers, Cj" uniqKey="Leugers C">CJ Leugers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hong, M" uniqKey="Hong M">M Hong</name></author><author><name sortKey="Zhukareva, V" uniqKey="Zhukareva V">V Zhukareva</name></author><author><name sortKey="Vogelsberg Ragaglia, V" uniqKey="Vogelsberg Ragaglia V">V Vogelsberg-Ragaglia</name></author><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24367683</article-id><article-id pub-id-type="pmc">3868614</article-id><article-id pub-id-type="publisher-id">PONE-D-13-25836</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0084615</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title> Overexpression of 14-3-3ζ Promotes Tau Phosphorylation at Ser<sup>262</sup> and Accelerates Proteosomal Degradation of Synaptophysin in Rat Primary Hippocampal Neurons</article-title><alt-title alt-title-type="running-head">Proteosomal Degradation of Synaptophysin</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Qureshi</surname><given-names>Hamid Y.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Han</surname><given-names>Dong</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>MacDonald</surname><given-names>Ryen</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Paudel</surname><given-names>Hemant K.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label> The<addr-line>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Skoulakis</surname><given-names>Efthimios M. C.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Alexander Fleming Biomedical Sciences Research Center, Greece</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>hemant.paudel@mcgill.ca</email></corresp><fn fn-type="conflict"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.
</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: HQ DH HP. Performed the experiments: HQ DH. Analyzed the data: HQ DH HP RM. Contributed reagents/materials/analysis tools: HP. Wrote the manuscript: HQ DH HP RM. </p></fn></author-notes><pub-date pub-type="collection"><year>2013</year></pub-date><pub-date pub-type="epub"><day>19</day><month>12</month><year>2013</year></pub-date><pub-date pub-type="ecorrected"><day>24</day><month>6</month><year>2014</year></pub-date><volume>8</volume><issue>12</issue><elocation-id>e84615</elocation-id><history><date date-type="received"><day>21</day><month>6</month><year>2013</year></date><date date-type="accepted"><day>15</day><month>11</month><year>2013</year></date></history><permissions><copyright-year>2013</copyright-year><copyright-holder>Qureshi et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>β-amyloid peptide accumulation, tau hyperphosphorylation, and synapse loss are characteristic neuropathological symptoms of Alzheimer’s disease (AD). Tau hyperphosphorylation is suggested to inhibit the association of tau with microtubules, making microtubules unstable and causing neurodegeneration. The mechanism of tau phosphorylation in AD brain, therefore, is of considerable significance. Although PHF-tau is phosphorylated at over 40 Ser/Thr sites, Ser<sup>262</sup> phosphorylation was shown to mediate β-amyloid neurotoxicity and formation of toxic tau lesions in the brain. <italic>In vitro</italic>, PKA is one of the kinases that phosphorylates <named-content content-type="gene">tau at</named-content> Ser<sup>262</sup>, but the mechanism by which it phosphorylates tau in AD brain is not very clear. 14-3-3ζ is associated with neurofibrillary tangles and is upregulated in AD brain. In this study, we show that 14-3-3ζ promotes tau phosphorylation at Ser<sup>262</sup> by PKA in differentiating neurons. When overexpressed in rat hippocampal primary neurons, 14-3-3ζ causes an increase in Ser<sup>262</sup> phosphorylation, a decrease in the amount of microtubule-bound tau, a reduction in the amount of polymerized microtubules, as well as microtubule instability. More importantly, the level of pre-synaptic protein synaptophysin was significantly reduced. Downregulation of synaptophysin in 14-3-3ζ overexpressing neurons was mitigated by inhibiting the proteosome, indicating that 14-3-3ζ promotes proteosomal degradation of synaptophysin. When 14-3-3ζ overexpressing neurons were treated with the microtubule stabilizing drug taxol, tau Ser<sup>262</sup> phosphorylation decreased and synaptophysin level was restored. Our data demonstrate that overexpression of 14-3-3ζ accelerates proteosomal turnover of synaptophysin by promoting the destabilization of microtubules. Synaptophysin is involved in synapse formation and neurotransmitter release. Our results suggest that 14-3-3ζ may cause synaptic pathology by reducing synaptophysin levels in the brains of patients suffering from AD. </p></abstract><funding-group><funding-statement>This work was supported by grants from Canadian Institute for Health Research, and Alzheimer’s Society of Canada. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group></article-meta></front></pmc><affiliations><list><country><li>Canada</li></country><region><li>Québec</li></region><settlement><li>Montréal</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><country name="Canada"><noRegion><name sortKey="Qureshi, Hamid Y" sort="Qureshi, Hamid Y" uniqKey="Qureshi H" first="Hamid Y." last="Qureshi">Hamid Y. Qureshi</name></noRegion><name sortKey="Han, Dong" sort="Han, Dong" uniqKey="Han D" first="Dong" last="Han">Dong Han</name><name sortKey="Macdonald, Ryen" sort="Macdonald, Ryen" uniqKey="Macdonald R" first="Ryen" last="Macdonald">Ryen Macdonald</name><name sortKey="Macdonald, Ryen" sort="Macdonald, Ryen" uniqKey="Macdonald R" first="Ryen" last="Macdonald">Ryen Macdonald</name><name sortKey="Paudel, Hemant K" sort="Paudel, Hemant K" uniqKey="Paudel H" first="Hemant K." last="Paudel">Hemant K. Paudel</name><name sortKey="Paudel, Hemant K" sort="Paudel, Hemant K" uniqKey="Paudel H" first="Hemant K." last="Paudel">Hemant K. Paudel</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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