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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Controlled enzymatic production of astrocytic hydrogen peroxide protects neurons from oxidative stress via an Nrf2-independent pathway</title><author><name sortKey="Haskew Layton, Renee E" sort="Haskew Layton, Renee E" uniqKey="Haskew Layton R" first="Renée E." last="Haskew-Layton">Renée E. Haskew-Layton</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Payappilly, Jimmy B" sort="Payappilly, Jimmy B" uniqKey="Payappilly J" first="Jimmy B." last="Payappilly">Jimmy B. Payappilly</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Smirnova, Natalya A" sort="Smirnova, Natalya A" uniqKey="Smirnova N" first="Natalya A." last="Smirnova">Natalya A. Smirnova</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Ma, Thong C" sort="Ma, Thong C" uniqKey="Ma T" first="Thong C." last="Ma">Thong C. Ma</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Chan, Kelvin K" sort="Chan, Kelvin K" uniqKey="Chan K" first="Kelvin K." last="Chan">Kelvin K. Chan</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Murphy, Timothy H" sort="Murphy, Timothy H" uniqKey="Murphy T" first="Timothy H." last="Murphy">Timothy H. Murphy</name><affiliation><nlm:aff id="aff2">Kinsmen Laboratory of Neurological Research, Department of Psychiatry,<institution>University of British Columbia</institution>, Vancouver, BC,<country>Canada</country> V6T 1Z3;</nlm:aff></affiliation></author><author><name sortKey="Guo, Hengchang" sort="Guo, Hengchang" uniqKey="Guo H" first="Hengchang" last="Guo">Hengchang Guo</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Langley, Brett" sort="Langley, Brett" uniqKey="Langley B" first="Brett" last="Langley">Brett Langley</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Sultana, Rukhsana" sort="Sultana, Rukhsana" uniqKey="Sultana R" first="Rukhsana" last="Sultana">Rukhsana Sultana</name><affiliation><nlm:aff id="aff3">Department of Chemistry, Sanders-Brown Center on Aging,<institution>University of Kentucky</institution>, Lexington, KY 40536;</nlm:aff></affiliation></author><author><name sortKey="Butterfield, D Allan" sort="Butterfield, D Allan" uniqKey="Butterfield D" first="D. Allan" last="Butterfield">D. Allan Butterfield</name><affiliation><nlm:aff id="aff3">Department of Chemistry, Sanders-Brown Center on Aging,<institution>University of Kentucky</institution>, Lexington, KY 40536;</nlm:aff></affiliation></author><author><name sortKey="Santagata, Sandro" sort="Santagata, Sandro" uniqKey="Santagata S" first="Sandro" last="Santagata">Sandro Santagata</name><affiliation><nlm:aff id="aff4">The Whitehead Institute for Biomedical Research, Cambridge, MA 02142;</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut="; and" id="aff5">Department of Pathology, Brigham and Women's Hospital<institution>Harvard Medical School</institution>, Boston, MA 02115</nlm:aff></affiliation></author><author><name sortKey="Alldred, Melissa J" sort="Alldred, Melissa J" uniqKey="Alldred M" first="Melissa J." last="Alldred">Melissa J. Alldred</name><affiliation><nlm:aff id="aff6">Center for Dementia Research, Nathan Kline Institute and the<institution>New York University Langone Medical Center</institution>, Orangeburg, NY 10962</nlm:aff></affiliation></author><author><name sortKey="Gazaryan, Irina G" sort="Gazaryan, Irina G" uniqKey="Gazaryan I" first="Irina G." last="Gazaryan">Irina G. Gazaryan</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Bell, George W" sort="Bell, George W" uniqKey="Bell G" first="George W." last="Bell">George W. Bell</name><affiliation><nlm:aff id="aff4">The Whitehead Institute for Biomedical Research, Cambridge, MA 02142;</nlm:aff></affiliation></author><author><name sortKey="Ginsberg, Stephen D" sort="Ginsberg, Stephen D" uniqKey="Ginsberg S" first="Stephen D." last="Ginsberg">Stephen D. Ginsberg</name><affiliation><nlm:aff id="aff6">Center for Dementia Research, Nathan Kline Institute and the<institution>New York University Langone Medical Center</institution>, Orangeburg, NY 10962</nlm:aff></affiliation></author><author><name sortKey="Ratan, Rajiv R" sort="Ratan, Rajiv R" uniqKey="Ratan R" first="Rajiv R." last="Ratan">Rajiv R. Ratan</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20855618</idno><idno type="pmc">2951414</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951414</idno><idno type="RBID">PMC:2951414</idno><idno type="doi">10.1073/pnas.1003996107</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000656</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000656</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Controlled enzymatic production of astrocytic hydrogen peroxide protects neurons from oxidative stress via an Nrf2-independent pathway</title><author><name sortKey="Haskew Layton, Renee E" sort="Haskew Layton, Renee E" uniqKey="Haskew Layton R" first="Renée E." last="Haskew-Layton">Renée E. Haskew-Layton</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Payappilly, Jimmy B" sort="Payappilly, Jimmy B" uniqKey="Payappilly J" first="Jimmy B." last="Payappilly">Jimmy B. Payappilly</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Smirnova, Natalya A" sort="Smirnova, Natalya A" uniqKey="Smirnova N" first="Natalya A." last="Smirnova">Natalya A. Smirnova</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Ma, Thong C" sort="Ma, Thong C" uniqKey="Ma T" first="Thong C." last="Ma">Thong C. Ma</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Chan, Kelvin K" sort="Chan, Kelvin K" uniqKey="Chan K" first="Kelvin K." last="Chan">Kelvin K. Chan</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Murphy, Timothy H" sort="Murphy, Timothy H" uniqKey="Murphy T" first="Timothy H." last="Murphy">Timothy H. Murphy</name><affiliation><nlm:aff id="aff2">Kinsmen Laboratory of Neurological Research, Department of Psychiatry,<institution>University of British Columbia</institution>, Vancouver, BC,<country>Canada</country> V6T 1Z3;</nlm:aff></affiliation></author><author><name sortKey="Guo, Hengchang" sort="Guo, Hengchang" uniqKey="Guo H" first="Hengchang" last="Guo">Hengchang Guo</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Langley, Brett" sort="Langley, Brett" uniqKey="Langley B" first="Brett" last="Langley">Brett Langley</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Sultana, Rukhsana" sort="Sultana, Rukhsana" uniqKey="Sultana R" first="Rukhsana" last="Sultana">Rukhsana Sultana</name><affiliation><nlm:aff id="aff3">Department of Chemistry, Sanders-Brown Center on Aging,<institution>University of Kentucky</institution>, Lexington, KY 40536;</nlm:aff></affiliation></author><author><name sortKey="Butterfield, D Allan" sort="Butterfield, D Allan" uniqKey="Butterfield D" first="D. Allan" last="Butterfield">D. Allan Butterfield</name><affiliation><nlm:aff id="aff3">Department of Chemistry, Sanders-Brown Center on Aging,<institution>University of Kentucky</institution>, Lexington, KY 40536;</nlm:aff></affiliation></author><author><name sortKey="Santagata, Sandro" sort="Santagata, Sandro" uniqKey="Santagata S" first="Sandro" last="Santagata">Sandro Santagata</name><affiliation><nlm:aff id="aff4">The Whitehead Institute for Biomedical Research, Cambridge, MA 02142;</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut="; and" id="aff5">Department of Pathology, Brigham and Women's Hospital<institution>Harvard Medical School</institution>, Boston, MA 02115</nlm:aff></affiliation></author><author><name sortKey="Alldred, Melissa J" sort="Alldred, Melissa J" uniqKey="Alldred M" first="Melissa J." last="Alldred">Melissa J. Alldred</name><affiliation><nlm:aff id="aff6">Center for Dementia Research, Nathan Kline Institute and the<institution>New York University Langone Medical Center</institution>, Orangeburg, NY 10962</nlm:aff></affiliation></author><author><name sortKey="Gazaryan, Irina G" sort="Gazaryan, Irina G" uniqKey="Gazaryan I" first="Irina G." last="Gazaryan">Irina G. Gazaryan</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author><author><name sortKey="Bell, George W" sort="Bell, George W" uniqKey="Bell G" first="George W." last="Bell">George W. Bell</name><affiliation><nlm:aff id="aff4">The Whitehead Institute for Biomedical Research, Cambridge, MA 02142;</nlm:aff></affiliation></author><author><name sortKey="Ginsberg, Stephen D" sort="Ginsberg, Stephen D" uniqKey="Ginsberg S" first="Stephen D." last="Ginsberg">Stephen D. Ginsberg</name><affiliation><nlm:aff id="aff6">Center for Dementia Research, Nathan Kline Institute and the<institution>New York University Langone Medical Center</institution>, Orangeburg, NY 10962</nlm:aff></affiliation></author><author><name sortKey="Ratan, Rajiv R" sort="Ratan, Rajiv R" uniqKey="Ratan R" first="Rajiv R." last="Ratan">Rajiv R. Ratan</name><affiliation><nlm:aff id="aff1">The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Neurons rely on their metabolic coupling with astrocytes to combat oxidative stress. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) appears important for astrocyte-dependent neuroprotection from oxidative insults. Indeed, Nrf2 activators are effective in stroke, Parkinson disease, and Huntington disease models. However, key endogenous signals that initiate adaptive neuroprotective cascades in astrocytes, including activation of Nrf2-mediated gene expression, remain unclear. Hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) plays an important role in cell signaling and is an attractive candidate mediator of adaptive responses in astrocytes. Here we determine (<italic>i</italic>) the significance of H<sub>2</sub>O<sub>2</sub> in promoting astrocyte-dependent neuroprotection from oxidative stress, and (<italic>ii</italic>) the relevance of H<sub>2</sub>O<sub>2</sub> in inducing astrocytic Nrf2 activation. To control the duration and level of cytoplasmic H<sub>2</sub>O<sub>2</sub> production in astrocytes cocultured with neurons, we heterologously expressed the H<sub>2</sub>O<sub>2</sub>-producing enzyme <italic>Rhodotorula gracilis</italic> D-amino acid oxidase (rgDAAO) selectively in astrocytes. Exposure of rgDAAO-astrocytes to D-alanine lead to the concentration-dependent generation of H<sub>2</sub>O<sub>2</sub>. Seven hours of low-level H<sub>2</sub>O<sub>2</sub> production (∼3.7 nmol·min·mg protein) in astrocytes protected neurons from oxidative stress, but higher levels (∼130 nmol·min·mg protein) were neurotoxic. Neuroprotection occurred without direct neuronal exposure to astrocyte-derived H<sub>2</sub>O<sub>2</sub>, suggesting a mechanism specific to astrocytic intracellular signaling. Nrf2 activation mimicked the effect of astrocytic H<sub>2</sub>O<sub>2</sub> yet H<sub>2</sub>O<sub>2</sub>-induced protection was independent of Nrf2. Astrocytic protein tyrosine phosphatase inhibition also protected neurons from oxidative death, representing a plausible mechanism for H<sub>2</sub>O<sub>2</sub>-induced neuroprotection. These findings demonstrate the utility of rgDAAO for spatially and temporally controlling intracellular H<sub>2</sub>O<sub>2</sub> concentrations to uncover unique astrocyte-dependent neuroprotective mechanisms.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">20855618</article-id><article-id pub-id-type="pmc">2951414</article-id><article-id pub-id-type="publisher-id">201003996</article-id><article-id pub-id-type="doi">10.1073/pnas.1003996107</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Neuroscience</subject></subj-group></subj-group></article-categories><title-group><article-title>Controlled enzymatic production of astrocytic hydrogen peroxide protects neurons from oxidative stress via an Nrf2-independent pathway</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Haskew-Layton</surname><given-names>Renée E.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Payappilly</surname><given-names>Jimmy B.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Smirnova</surname><given-names>Natalya A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Ma</surname><given-names>Thong C.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chan</surname><given-names>Kelvin K.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Murphy</surname><given-names>Timothy H.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Guo</surname><given-names>Hengchang</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Langley</surname><given-names>Brett</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sultana</surname><given-names>Rukhsana</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Butterfield</surname><given-names>D. Allan</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Santagata</surname><given-names>Sandro</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Alldred</surname><given-names>Melissa J.</given-names></name><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gazaryan</surname><given-names>Irina G.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bell</surname><given-names>George W.</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ginsberg</surname><given-names>Stephen D.</given-names></name><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ratan</surname><given-names>Rajiv R.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><aff id="aff1"><sup>a</sup>The Burke Medical Research Institute, Department of Neurology and Neuroscience,<institution>Weill Medical College of Cornell University</institution>, White Plains, NY 10605;</aff><aff id="aff2"><sup>b</sup>Kinsmen Laboratory of Neurological Research, Department of Psychiatry,<institution>University of British Columbia</institution>, Vancouver, BC,<country>Canada</country> V6T 1Z3;</aff><aff id="aff3"><sup>c</sup>Department of Chemistry, Sanders-Brown Center on Aging,<institution>University of Kentucky</institution>, Lexington, KY 40536;</aff><aff id="aff4"><sup>d</sup>The Whitehead Institute for Biomedical Research, Cambridge, MA 02142;</aff><aff id="aff5"><sup>e</sup>Department of Pathology, Brigham and Women's Hospital and<institution>Harvard Medical School</institution>, Boston, MA 02115; and</aff><aff id="aff6"><sup>f</sup>Center for Dementia Research, Nathan Kline Institute and the<institution>New York University Langone Medical Center</institution>, Orangeburg, NY 10962</aff></contrib-group><author-notes><corresp id="cor1"><sup>1</sup>To whom correspondence may be addressed. E-mail: <email>rrr2001@med.cornell.edu</email> or <email>rhaskew@burke.org</email>.</corresp><fn fn-type="edited-by"><p>Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 24, 2010 (received for review March 26, 2010)</p></fn><fn fn-type="con"><p>Author contributions: R.E.H.-L., J.B.P., N.A.S., H.G., B.L., S.S., M.J.A., I.G.G., S.D.G., and R.R.R. designed research; R.E.H.-L., J.B.P., N.A.S., T.C.M., K.K.C., H.G., B.L., S.S., and M.J.A. performed research; R.E.H.-L., N.A.S., T.C.M., T.H.M., B.L., R.S., D.A.B., I.G.G., and R.R.R. contributed new reagents/analytic tools; R.E.H.-L., T.C.M., K.K.C., S.S., G.W.B., S.D.G., and R.R.R. analyzed data; and R.E.H.-L., J.B.P., I.G.G., and R.R.R. wrote the paper.</p></fn></author-notes><pub-date pub-type="ppub"><day>5</day><month>10</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>20</day><month>9</month><year>2010</year></pub-date><pub-date pub-type="pmc-release"><day>20</day><month>9</month><year>2010</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>107</volume><issue>40</issue><fpage>17385</fpage><lpage>17390</lpage><permissions><license license-type="open-access"><license-p>Freely available online through the PNAS open access option.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="pnas.201003996.pdf"></self-uri><abstract><p>Neurons rely on their metabolic coupling with astrocytes to combat oxidative stress. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) appears important for astrocyte-dependent neuroprotection from oxidative insults. Indeed, Nrf2 activators are effective in stroke, Parkinson disease, and Huntington disease models. However, key endogenous signals that initiate adaptive neuroprotective cascades in astrocytes, including activation of Nrf2-mediated gene expression, remain unclear. Hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) plays an important role in cell signaling and is an attractive candidate mediator of adaptive responses in astrocytes. Here we determine (<italic>i</italic>) the significance of H<sub>2</sub>O<sub>2</sub> in promoting astrocyte-dependent neuroprotection from oxidative stress, and (<italic>ii</italic>) the relevance of H<sub>2</sub>O<sub>2</sub> in inducing astrocytic Nrf2 activation. To control the duration and level of cytoplasmic H<sub>2</sub>O<sub>2</sub> production in astrocytes cocultured with neurons, we heterologously expressed the H<sub>2</sub>O<sub>2</sub>-producing enzyme <italic>Rhodotorula gracilis</italic> D-amino acid oxidase (rgDAAO) selectively in astrocytes. Exposure of rgDAAO-astrocytes to D-alanine lead to the concentration-dependent generation of H<sub>2</sub>O<sub>2</sub>. Seven hours of low-level H<sub>2</sub>O<sub>2</sub> production (∼3.7 nmol·min·mg protein) in astrocytes protected neurons from oxidative stress, but higher levels (∼130 nmol·min·mg protein) were neurotoxic. Neuroprotection occurred without direct neuronal exposure to astrocyte-derived H<sub>2</sub>O<sub>2</sub>, suggesting a mechanism specific to astrocytic intracellular signaling. Nrf2 activation mimicked the effect of astrocytic H<sub>2</sub>O<sub>2</sub> yet H<sub>2</sub>O<sub>2</sub>-induced protection was independent of Nrf2. Astrocytic protein tyrosine phosphatase inhibition also protected neurons from oxidative death, representing a plausible mechanism for H<sub>2</sub>O<sub>2</sub>-induced neuroprotection. These findings demonstrate the utility of rgDAAO for spatially and temporally controlling intracellular H<sub>2</sub>O<sub>2</sub> concentrations to uncover unique astrocyte-dependent neuroprotective mechanisms.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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