title: Alterations of ubiquitin related proteins in the pathology and development of schizophrenia: Evidence from human and animal studies.
abstract: Gene expression analyses in post-mortem schizophrenia brains suggest that a number of ubiquitin proteasome system (UPS) genes are associated with schizophrenia; however the status of UPS proteins in the schizophrenia brain is largely unknown. Ubiquitin related proteins are inherently involved in memory, neuronal survival and morphology, which are processes implicated in neurodevelopmental disorders such as schizophrenia. We examined levels of five UPS proteins (Protein Inhibitor of Activated STAT2 [PIAS2], F-Box and Leucine rich repeat protein 21 [FBXL21], Mouse Double Minute 2 homolog [MDM2], Ubiquitin Carboxyl-Terminal Hydrolase-L1 [UCHL1] and Ubiquitin Conjugating Enzyme E2D1 [UBE2D1]) involved in these neuronal processes, within the dorsolateral prefrontal cortex of post-mortem schizophrenia subjects and matched controls (n = 30/group), in addition to across neurodevelopmental time-points (juvenile, adolescent and adult stages of life), utilizing a well-established neurodevelopmental phencyclidine (PCP) animal model of schizophrenia. We observed significant reductions in PIAS2, FBXL21 and MDM2 in schizophrenia subjects compared to controls (p-values ranging from 0.002 to 0.004). In our developmental PCP model, MDM2 protein was significantly reduced in adult PCP-treated rats compared to controls (p = 0.034). Additionally, FBXL21 (p = 0.022) and UCHL1 (p = 0.022) were significantly decreased, whilst UBE2D1 was increased (p = 0.022), in juvenile phencyclidine-treated rats compared to controls. This is the first study reporting alterations of UPS proteins in post-mortem human schizophrenia subjects and in a neurodevelopmental model of schizophrenia. The findings from this study provide strong support for a role of these UPS proteins in the pathology and development of schizophrenia.
authors.affiliation: Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia; Schizophrenia Research Institute, Sydney, NSW 2010, Australia. Electronic address: ja393@uowmail.edu.au.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Andrews
authors.affiliation: Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia. Electronic address: fjg399@uowmail.edu.au.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Goodfellow
authors.affiliation: Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia; Schizophrenia Research Institute, Sydney, NSW 2010, Australia. Electronic address: natalie_matosin@uow.edu.au.
authors.forename: Natalie
authors.initials: N
authors.lastname: Matosin
authors.affiliation: Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia. Electronic address: ms621@uowmail.edu.au.
authors.forename: Mollie K
authors.initials: MK
authors.lastname: Snelling
authors.affiliation: Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia; Schizophrenia Research Institute, Sydney, NSW 2010, Australia. Electronic address: knewell@uow.edu.au.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Newell
authors.affiliation: Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia; Schizophrenia Research Institute, Sydney, NSW 2010, Australia. Electronic address: xhuang@uow.edu.au.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
authors.affiliation: Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia; Schizophrenia Research Institute, Sydney, NSW 2010, Australia; Faculty of Social Sciences, University of Wollongong, Wollongong, NSW 2522, Australia. Electronic address: fernande@uow.edu.au.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fernandez-Enright
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D044783:F-Box Proteins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010622:Phencyclidine / Q000633:toxicity; D011180:Postmortem Changes; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D044783:F-Box Proteins; C532948:FBXL21P protein, human; C501001:PIAS2 protein, human; D050828:Protein Inhibitors of Activated STAT; D014452:Ubiquitins; C097308:UBE2D1 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D051736:Proto-Oncogene Proteins c-mdm2; D043222:Ubiquitin Thiolesterase; D010622:Phencyclidine
keywords: E2 ubiquitin conjugating enzyme; E3 ligases; Human brain cohort; Neurodevelopmental animal model; Schizophrenia