title: Oxidative stress reduces levels of dysbindin-1A via its PEST domain.
abstract: Oxidative stress resulting from the generation of reactive oxygen species has been proposed as an etiological factor in schizophrenia. The present study tests the hypothesis that oxidative stress can affect levels of dysbindin-1A, encoded by Dtnbp1, a genetic risk factor for schizophrenia, via its PEST domain. In vitro studies on SH-SY5Y cells indicate that oxidative stress triggers proteasomal degradation of dysbindin-1A, and that this requires interactions with its PEST domain, which may be a TRIM32 target. We specifically found (a) that oxidative stress induced in SH-SY5Y cells by 500 µM hydrogen peroxide reduced levels of full-length dysbindin-1, but did not reduce levels of that protein lacking its PEST domain and (b) that levels of full-length dysbindin-1, but not dysbindin-1 lacking its PEST domain, were higher in cells treated with the proteasome inhibitor MG132. Oxidative stress thus emerges as the first known cellular factor regulating dysbindin-1 isoforms with PEST domains. These findings are consistent with the previously noted fact that phosphorylation of PEST domains often marks proteins for proteasomal degradation, and raises the possibility that treatments reducing oxidative stress in the brain, especially during development, may lower schizophrenia risk.
authors.affiliation: Department of Anatomy, National University of Singapore, Singapore 119260.
authors.forename: Mei-Yi Alicia
authors.initials: MY
authors.lastname: Yap
authors.affiliation: Department of Anatomy, National University of Singapore, Singapore 119260; Division of Neurology, National Neuroscience Institute, Singapore General Hospital Campus, Singapore 169608.
authors.forename: Yew-Long
authors.initials: YL
authors.lastname: Lo
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Advanced Health Sciences Pavilion, Los Angeles, CA 90048, USA.
authors.forename: Konrad
authors.initials: K
authors.lastname: Talbot
authors.affiliation: Department of Anatomy, National University of Singapore, Singapore 119260; Neurobiology and Ageing Research Programme, National University of Singapore, Singapore 119260. Electronic address: wei_yi_ong@nuhs.edu.sg.
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Ong
mesh_terms: D000818:Animals; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012559:Schizophrenia / Q000378:metabolism
chemical_list: D015853:Cysteine Proteinase Inhibitors; C574928:Dtnbp1 protein, rat; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D007976:Leupeptins; D017382:Reactive Oxygen Species; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Dysbindin; Oxidative stress; PEST domain; Proteasome; Schizophrenia