{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T03:03:41Z","timestamp":1791169421054,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,2,25]],"date-time":"2015-02-25T00:00:00Z","timestamp":1424822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Intramural Research Program of the National Institute of Neurological Disorders and Stroke"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2015,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Repeated systemic administration of the mitochondrial complex I inhibitor rotenone produces a rodent model of Parkinson's disease (PD). Mechanisms of relatively selective rotenone\u2010induced damage to nigrostriatal dopaminergic neurons remain incompletely understood. According to the \u2018catecholaldehyde hypothesis,\u2019 buildup of the autotoxic dopamine metabolite 3,4\u2010dihydroxyphenylacetaldehyde (DOPAL) contributes to PD pathogenesis. Vesicular uptake blockade increases DOPAL levels, and DOPAL is detoxified mainly by aldehyde dehydrogenase (ALDH). We tested whether rotenone interferes with vesicular uptake and intracellular ALDH activity. Endogenous and F\u2010labeled catechols were measured in PC12 cells incubated with rotenone (0\u20131000\u00a0nM, 180\u00a0min), without or with F\u2010dopamine (2\u00a0\u03bcM) to track vesicular uptake and catecholamine metabolism. Rotenone dose dependently increased DOPAL, F\u2010DOPAL, and 3,4\u2010dihydroxyphenylethanol (DOPET) levels while decreasing dopamine and 3,4\u2010dihydroxyphenylacetic acid (DOPAC) levels and the ratio of dopamine to the sum of its deaminated metabolites. In test tubes, rotenone did not affect conversion of DOPAL to DOPAC by ALDH when NAD\n                    <jats:sup>+<\/jats:sup>\n                    was supplied, whereas the direct\u2010acting ALDH inhibitor benomyl markedly increased DOPAL and decreased DOPAC concentrations in the reaction mixtures. We propose that rotenone builds up intracellular DOPAL by decreasing ALDH activity and attenuating vesicular sequestration of cytoplasmic catecholamines. The results provide a novel mechanism for selective rotenone\u2010induced toxicity in dopaminergic neurons.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13042-fig-0011-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>\n                  <jats:p>We report that rotenone, a mitochondrial complex I inhibitor that produces an animal model of Parkinson's disease, increases intracelular levels of the toxic dopamine metabolite 3,4\u2010dihydroxyphenyl\u2010acetaldehyde (DOPAL), via decreased DOPAL metabolism by aldehyde dehydrogenase (ALDH) and decreased vesicular sequestration of cytoplasmic dopamine by the vesicular monoamine transporter (VMAT). The results provide a novel mechanism for rotenone\u2010induced toxicity in dopaminergic neurons.<\/jats:p>","DOI":"10.1111\/jnc.13042","type":"journal-article","created":{"date-parts":[[2015,1,27]],"date-time":"2015-01-27T08:25:18Z","timestamp":1422347118000},"page":"14-25","source":"Crossref","is-referenced-by-count":46,"title":["Rotenone decreases intracellular aldehyde dehydrogenase activity: implications for the pathogenesis of Parkinson's disease"],"prefix":"10.1111","volume":"133","author":[{"given":"David S.","family":"Goldstein","sequence":"first","affiliation":[{"name":"Clinical Neurocardiology Section CNP\/DIR\/NINDS\/NIH Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patti","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Clinical Neurocardiology Section CNP\/DIR\/NINDS\/NIH Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adele","family":"Cooney","sequence":"additional","affiliation":[{"name":"Clinical Neurocardiology Section CNP\/DIR\/NINDS\/NIH Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunden","family":"Jinsmaa","sequence":"additional","affiliation":[{"name":"Clinical Neurocardiology Section CNP\/DIR\/NINDS\/NIH Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irwin J.","family":"Kopin","sequence":"additional","affiliation":[{"name":"Clinical Neurocardiology Section CNP\/DIR\/NINDS\/NIH Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehonatan","family":"Sharabi","sequence":"additional","affiliation":[{"name":"Hypertension Unit Chaim Sheba Medical Center and Tel\u2010Aviv University Tel\u2010HaShomer Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,2,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.249532"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/81834"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(03)03354-7"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-007-0303-9"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx5002223"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2014.09.016"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2005.7.630"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2010.05906.x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(97)00008-5"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1220399110"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000083"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2012.07924.x"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12345"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2014.06.006"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12766"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410270405"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2003.01533.x"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(93)E0430-X"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2014.03.016"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.65.12.1577"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198804073181402"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4547(20000515)60:4<552::AID-JNR14>3.0.CO;2-U"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)02309-X"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.21855"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuro.2006.08.008"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1745-7254.2005.00003.x"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx049843k"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015251"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2008.04.019"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.2002.8072"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.67"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.1002839"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1054-3589(08)60740-1"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2013.08.033"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.127597"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.108.048546"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2011.08.041"}],"container-title":["Journal 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