{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T04:03:06Z","timestamp":1768536186121,"version":"3.49.0"},"reference-count":45,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2014,1,21]],"date-time":"2014-01-21T00:00:00Z","timestamp":1390262400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NRF","award":["2013-008773"],"award-info":[{"award-number":["2013-008773"]}]},{"name":"NRF","award":["2010-0009233"],"award-info":[{"award-number":["2010-0009233"]}]},{"name":"Ewha Global Top 5","award":["2012-1781-001"],"award-info":[{"award-number":["2012-1781-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2014,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Abnormal autophagy may contribute to neurodegeneration in Parkinson's disease (PD). However, it is largely unknown how autophagy is dysregulated by oxidative stress (OS), one of major pathogenic causes of PD. We recently discovered the potential autophagy regulator gene family including Tnfaip8\/Oxi\u2010\u03b1, which is a mammalian target of rapamycin (<jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>) activator down\u2010regulated by OS in dopaminergic neurons (<jats:italic>J. Neurochem<\/jats:italic>., 112, 2010<jats:bold>,<\/jats:bold> 366). Here, we demonstrate that the OS\u2010induced Tnfaip8\u00a0l1\/Oxi\u2010\u03b2 could increase autophagy by a unique mechanism that increases the stability of tuberous sclerosis complex 2 (TSC2), a critical negative regulator of <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>. Tnfaip8\u00a0l1\/Oxi\u2010\u03b2 and Tnfaip8\/Oxi\u2010\u03b1 are the novel regulators of <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> acting in opposition in dopaminergic (DA) neurons. Specifically, 6\u2010hydroxydopamine (6\u2010OHDA) treatment up\u2010regulated Tnfaip8\u00a0l1\/Oxi\u2010\u03b2 in DA neurons, thus inducing autophagy, while knockdown of Tnfaip8\u00a0l1\/Oxi\u2010\u03b2 prevented significantly activation of autophagic markers by 6\u2010OHDA. FBXW5 was identified as a novel binding protein for Tnfaip8\u00a0l1\/Oxi\u2010\u03b2. FBXW5 is a TSC2 binding receptor within CUL4 E3 ligase complex, and it promotes proteasomal degradation of TSC2. Thus, Tnfaip8\u00a0l1\/Oxi\u2010\u03b2 competes with TSC2 to bind FBXW5, increasing TSC2 stability by preventing its ubiquitination. Our data show that the OS\u2010induced Tnfaip8\u00a0l1\/Oxi\u2010\u03b2 stabilizes TSC2 protein, decreases <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> phosphorylation, and enhances autophagy. Therefore, altered regulation of Tnfaip8\u00a0l1\/Oxi\u2010\u03b2 may contribute significantly to dysregulated autophagy observed in dopaminergic neurons under pathogenic OS condition.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc12643-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>Dysfunctional autophagy is frequently observed in post\u2010mortem brains of patients and animal models of Parkinson's disease. In dopaminergic neurons of the 6\u2010hydroxydopamine (6\u2010OHDA) model, oxidative stress induces Tnfaip8\u00a0l1\/Oxi\u2010\u03b2, which results in increased autophagy by its exclusive binding with FBXW5 to stabilize TSC2. Thus, altered regulation of Tnfaip8\u00a0l1\/Oxi\u2010\u03b2 may contribute to dysregulated autophagy in dopaminergic neurons under pathogenic oxidative stress, implicating both Oxi\u2010\u03b2 and FBXW5 as potential intervention targets for dysfunctional autophagy in dopaminergic neurons under oxidative stress.<\/jats:p>","DOI":"10.1111\/jnc.12643","type":"journal-article","created":{"date-parts":[[2014,1,21]],"date-time":"2014-01-21T11:01:40Z","timestamp":1390302100000},"page":"527-538","source":"Crossref","is-referenced-by-count":52,"title":["Tnfaip8\u00a0l1\/Oxi\u2010\u03b2 binds to <scp>FBXW<\/scp>5, increasing autophagy through activation of <scp>TSC<\/scp>2 in a Parkinson's disease model"],"prefix":"10.1111","volume":"129","author":[{"given":"Ji\u2010Young","family":"Ha","sequence":"first","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences College of Pharmacy Seoul South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji\u2010Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences College of Pharmacy Seoul South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young\u2010Hee","family":"Kang","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences College of Pharmacy Seoul South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugene","family":"Bok","sequence":"additional","affiliation":[{"name":"Burnett School of Biomedical Science College of Medicine University of Central Florida Orlando FL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoon\u2010Seong","family":"Kim","sequence":"additional","affiliation":[{"name":"Burnett School of Biomedical Science College of Medicine University of Central Florida Orlando FL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin H.","family":"Son","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences College of Pharmacy Seoul South Korea"},{"name":"Department of Brain and Cognitive Sciences Brain Disease Research Institute Ewha Womans University Seoul South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,1,21]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"25","article-title":"Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease","volume":"12","author":"Anglade P.","year":"1997","journal-title":"Histol. 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