{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T19:58:25Z","timestamp":1788897505272,"version":"build-2803163510"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"40","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,10,5]]},"abstract":"<jats:p>\n                    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\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    ) plays an important role in cell signaling and is an attractive candidate mediator of adaptive responses in astrocytes. Here we determine (\n                    <jats:italic>i<\/jats:italic>\n                    ) the significance of H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    in promoting astrocyte-dependent neuroprotection from oxidative stress, and (\n                    <jats:italic>ii<\/jats:italic>\n                    ) the relevance of H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    in inducing astrocytic Nrf2 activation. To control the duration and level of cytoplasmic H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    production in astrocytes cocultured with neurons, we heterologously expressed the H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    -producing enzyme\n                    <jats:italic>Rhodotorula gracilis<\/jats:italic>\n                    D-amino acid oxidase (rgDAAO) selectively in astrocytes. Exposure of rgDAAO-astrocytes to D-alanine lead to the concentration-dependent generation of H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    . Seven hours of low-level H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    production (\u223c3.7 nmol\u00b7min\u00b7mg protein) in astrocytes protected neurons from oxidative stress, but higher levels (\u223c130 nmol\u00b7min\u00b7mg protein) were neurotoxic. Neuroprotection occurred without direct neuronal exposure to astrocyte-derived H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    , suggesting a mechanism specific to astrocytic intracellular signaling. Nrf2 activation mimicked the effect of astrocytic H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    yet H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    -induced protection was independent of Nrf2. Astrocytic protein tyrosine phosphatase inhibition also protected neurons from oxidative death, representing a plausible mechanism for H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    -induced neuroprotection. These findings demonstrate the utility of rgDAAO for spatially and temporally controlling intracellular H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    concentrations to uncover unique astrocyte-dependent neuroprotective mechanisms.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1003996107","type":"journal-article","created":{"date-parts":[[2010,9,21]],"date-time":"2010-09-21T00:37:18Z","timestamp":1285029438000},"page":"17385-17390","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":138,"title":["Controlled enzymatic production of astrocytic hydrogen peroxide protects neurons from oxidative stress via an Nrf2-independent pathway"],"prefix":"10.1073","volume":"107","author":[{"given":"Ren\u00e9e E.","family":"Haskew-Layton","sequence":"first","affiliation":[{"name":"The Burke Medical Research Institute, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY 10605;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy B.","family":"Payappilly","sequence":"additional","affiliation":[{"name":"The Burke Medical Research Institute, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY 10605;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalya A.","family":"Smirnova","sequence":"additional","affiliation":[{"name":"The Burke Medical Research Institute, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY 10605;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thong C.","family":"Ma","sequence":"additional","affiliation":[{"name":"The Burke Medical Research Institute, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY 10605;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin K.","family":"Chan","sequence":"additional","affiliation":[{"name":"The Burke Medical Research Institute, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY 10605;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy H.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengchang","family":"Guo","sequence":"additional","affiliation":[{"name":"The Burke Medical Research Institute, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY 10605;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Langley","sequence":"additional","affiliation":[{"name":"The Burke Medical Research Institute, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY 10605;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rukhsana","family":"Sultana","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Allan","family":"Butterfield","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandro","family":"Santagata","sequence":"additional","affiliation":[{"name":"The Whitehead Institute for Biomedical Research, Cambridge, MA 02142;"},{"name":"Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa J.","family":"Alldred","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan Kline Institute and the New York University Langone Medical Center, Orangeburg, NY 10962"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina G.","family":"Gazaryan","sequence":"additional","affiliation":[{"name":"The Burke Medical Research Institute, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY 10605;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George W.","family":"Bell","sequence":"additional","affiliation":[{"name":"The Whitehead Institute for Biomedical Research, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Ginsberg","sequence":"additional","affiliation":[{"name":"Center for Dementia Research, Nathan Kline Institute and the New York University Langone Medical Center, Orangeburg, NY 10962"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajiv R.","family":"Ratan","sequence":"additional","affiliation":[{"name":"The Burke Medical Research Institute, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY 10605;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,9,20]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2008.03.011"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1130481"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.270.5234.296"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600476"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1991.tb07761.x"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/35648"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.11.016"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00794-8"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1706-09.2009"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1434"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-08-03394.2003"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2009.07.035"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4099-08.2008"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813361106"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502402102"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211558200"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.014837"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04345.x"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5700585"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(02)01062-8"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.1998.9.2-185"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1994.62010376.x"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201000084"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0409289"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01080-08"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2008.09.027"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M611336200"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.051714"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0232966100"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2008.06.005"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.20402"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.092510"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707587"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2008.43"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20749"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-010-0447-y"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1826-08.2008"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(09)70054-7"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1003996107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T18:33:21Z","timestamp":1649788401000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1003996107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,9,20]]},"references-count":38,"journal-issue":{"issue":"40","published-print":{"date-parts":[[2010,10,5]]}},"alternative-id":["10.1073\/pnas.1003996107"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1003996107","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.5364968.5315068","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,9,20]]},"assertion":[{"value":"2010-09-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}