title: Dysfunction of the ubiquitin proteasome and ubiquitin-like systems in schizophrenia.
abstract: Protein expression abnormalities have been implicated in the pathophysiology of schizophrenia, but the underlying cause of these changes is not known. We sought to investigate ubiquitin and ubiquitin-like (UBL) systems (SUMOylation, NEDD8ylation, and Ufmylation) as putative mechanisms underlying protein expression abnormalities seen in schizophrenia. For this, we performed western blot analysis of total ubiquitination, free ubiquitin, K48- and K63-linked ubiquitination, and E1 activases, E2 conjugases, and E3 ligases involved in ubiquitination and UBL post-translational modifications in postmortem brain tissue samples from persons with schizophrenia (n=13) and comparison subjects (n=13). We studied the superior temporal gyrus (STG) of subjects from the Mount Sinai Medical Center brain collection that were matched for age, tissue pH, and sex. We found an overall reduction of protein ubiquitination, free ubiquitin, K48-linked ubiquitination, and increased K63 polyubiquitination in schizophrenia. Ubiquitin E1 activase UBA (ubiquitin activating enzyme)-6 and E3 ligase Nedd (neural precursor cell-expressed developmentally downregulated)-4 were decreased in this illness, as were E3 ligases involved in Ufmylation (UFL1) and SUMOylation (protein inhibitor of activated STAT 3, PIAS3). NEDD8ylation was also dysregulated in schizophrenia, with decreased levels of the E1 activase UBA3 and the E3 ligase Rnf7. This study of ubiquitin and UBL systems in schizophrenia found abnormalities of ubiquitination, Ufmylation, SUMOylation, and NEDD8ylation in the STG in this disorder. These results suggest a novel approach to the understanding of schizophrenia pathophysiology, where a disruption in homeostatic adaptation of the cell underlies discreet changes seen at the protein level in this illness.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0021, USA. mrubio@uab.edu
authors.forename: María D
authors.initials: MD
authors.lastname: Rubio
authors.forename: Krista
authors.initials: K
authors.lastname: Wood
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.forename: James H
authors.initials: JH
authors.lastname: Meador-Woodruff
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000378:metabolism; D000075687:NEDD8 Protein; D000075702:Nedd4 Ubiquitin Protein Ligases; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051381:Rats; D012559:Schizophrenia / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects; D058207:Sumoylation; D013702:Temporal Lobe / Q000201:enzymology*; D025801:Ubiquitin / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects*; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D018832:Molecular Chaperones; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D025801:Ubiquitin; D014452:Ubiquitins; C100879:UBE2K protein, human; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; D000075702:Nedd4 Ubiquitin Protein Ligases; D044767:Ubiquitin-Protein Ligases; D044764:Ubiquitin-Activating Enzymes; D006220:Haloperidol