{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T09:58:26Z","timestamp":1791367106023,"version":"4.3.1"},"reference-count":72,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T00:00:00Z","timestamp":1741132800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T00:00:00Z","timestamp":1741132800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:p>Parkinson's disease (PD) is a devastating neurodegenerative disorder with a distinct loss of the nigrostriatal dopaminergic pathway. Despite the multiplicity in etiology, alterations that disrupt neuronal integrity can be traced back to defects in fundamental processes that typically run under mitochondrial inputs. Evidence indicates that mitochondrial activities are hierarchically integrated with the energetic performance of these organelles, so that an interesting perspective holds that interventions aimed at improving mitochondrial bioenergetics can potentially mitigate the severity of PD phenotype expression. In this mechanistic framework, approaches that facilitate the mitochondrial anaplerotic use of glutamate (Glut) might counteract the detrimental shift from Glut metabolism, which is typically altered in PD, to excessive Glut transmission that feeds excitotoxicity and the neurodegenerative spiral. In this study, we investigated whether the enhancement of glutamate dehydrogenase (GDH) activity, by using the GDH activator 2\u2010aminobicyclo\u2010(2,2,1)\u2010heptane\u20102\u2010carboxylic acid (BCH), has neuroprotective potential against PD injury. In both retinoic acid\u2010differentiated SH\u2010SY5Y cells and primary rat mesencephalic neurons challenged with \u03b1\u2010synuclein plus rotenone to mimic PD, BCH\u2010dependent GDH activation significantly ameliorated cell viability, improved mitochondrial ATP synthesis and lessened to control levels the cellular redox burden. Strikingly, we collected evidence for the existence of a functional axis connecting GDH activity to a specific intracellular pool of the Excitatory Amino Acid Transporters (EAATs), namely the EAAT3. Overall, our results reveal a novel and non\u2010redundant role of EAAT3 for GDH\u2010dependent protection against PD injury, which may inspire new pharmacological approaches against PD pathology.<\/jats:p>","DOI":"10.1111\/febs.70053","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T12:14:24Z","timestamp":1741695264000},"page":"3224-3241","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A non\u2010redundant role of\n                    <scp>EAAT3<\/scp>\n                    for\n                    <scp>ATP<\/scp>\n                    synthesis mediated by\n                    <scp>GDH<\/scp>\n                    in dopaminergic neuronal cells: a new avenue for glutamate metabolism and protection in Parkinson's disease"],"prefix":"10.1111","volume":"292","author":[{"given":"Alessandra","family":"Preziuso","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences and Public Health School of Medicine, University \u201cPolitecnica delle Marche\u201d  Ancona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziano","family":"Serfilippi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Public Health School of Medicine, University \u201cPolitecnica delle Marche\u201d  Ancona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa","family":"Toujani","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Meyer Children's University Hospital  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Terenzi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Public Health School of Medicine, University \u201cPolitecnica delle Marche\u201d  Ancona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Amoroso","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Public Health School of Medicine, University \u201cPolitecnica delle Marche\u201d  Ancona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Magi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Public Health School of Medicine, University \u201cPolitecnica delle Marche\u201d  Ancona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1518-1495","authenticated-orcid":false,"given":"Vincenzo","family":"Lariccia","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Public Health School of Medicine, University \u201cPolitecnica delle Marche\u201d  Ancona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7608-5589","authenticated-orcid":false,"given":"Silvia","family":"Piccirillo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Public Health School of Medicine, University \u201cPolitecnica delle Marche\u201d  Ancona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,5]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232113043"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2017.03.009"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23169212"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25042009"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2022.105697"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jocn.2021.05.056"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.585584"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-81185-9"},{"key":"e_1_2_10_10_1","article-title":"Deep brain stimulation in the treatment of Parkinson's disease","volume":"14","author":"Shah H","year":"2022","journal-title":"Cureus"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2021.11.044"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M710012200"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1713849115"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64553-1"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2006.02.003"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531\u2010023\u201000561\u20106"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04422-2"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010023\u201006251\u20108"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2018.00301"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.crphar.2024.100187"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9092037"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20225674"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-013-1227-5"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2011.07.003"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2000.0751862.x"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.51.7.893"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1159\/000213026"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410150206"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00007757"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2016.11.007"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-11-0340"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.65.4.1008"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0784-6"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115886"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.084194"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-024-04192-y"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/s121115628"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14040764"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.113.087775"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0034015"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200317638"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2019.134652"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-017-0340-9"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-75361-6"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2011.01.014"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.3390\/metabo10110450"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.5607\/en.2015.24.2.103"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2020.102268"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2014.12.006"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X17714680"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22609"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23176"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23105"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-0186(03)00028-7"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2011.03.015"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-77375-5_2"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25084341"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-017-2428-0"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(00)00067-8"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-023-02624-6"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4413-09.2009"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2022.07.002"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2009.179"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-018-2467-1"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1990.tb01967.x"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0708930105"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.6b00979"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology12071005"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-022-01187-y"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2010.08.008"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-13478-x"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12394"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10082109"}],"container-title":["The FEBS Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/febs.70053","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/febs.70053","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/febs.70053","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T09:43:48Z","timestamp":1791366228000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1111\/febs.70053"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,5]]},"references-count":72,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1111\/febs.70053"],"URL":"https:\/\/doi.org\/10.1111\/febs.70053","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/FEBS.70053\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/FEBS.70053\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/FEBS.70053\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/FEBS.70053\/v2\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/FEBS.70053\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/FEBS.70053\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/FEBS.70053\/v1\/decision1","asserted-by":"object"}]},"ISSN":["1742-464X","1742-4658"],"issn-type":[{"value":"1742-464X","type":"print"},{"value":"1742-4658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,5]]},"assertion":[{"value":"2024-08-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}