title: Decreased protein S-palmitoylation in dorsolateral prefrontal cortex in schizophrenia.
abstract: Recent reports suggest abnormalities of neurotransmitter receptor trafficking, targeting, dendritic localization, recycling, and degradation in the brain in schizophrenia. We hypothesized that a potential explanation for these findings may be abnormal posttranslational modifications that influence intracellular targeting and trafficking of proteins between subcellular compartments. Dysregulation of protein palmitoylation is a strong candidate for such a process. S-palmitoylation is a reversible thioesterification of palmitoyl-groups to cysteine residues that can regulate trafficking and targeting of intracellular proteins. Using a biotin switch assay to study S-palmitoylation of proteins in human postmortem brain, we identified a pattern of palmitoylated proteins that cluster into 17 bands of discrete molecular masses, including numerous proteins associated with receptor signal transduction. Using mass spectrometry, we identified 219 palmitoylated proteins in human frontal cortex, and individually validated palmitoylation status of a subset of these proteins. Next, we assayed protein palmitoylation in dorsolateral prefrontal cortex from 16 schizophrenia patients and paired comparison subjects. S-palmitoylation was significantly reduced for proteins in most of the 17 schizophrenia bands. In rats chronically treated with haloperidol, the same pattern of palmitoylation was observed but the extent of palmitoylation was unchanged, suggesting that the diminution in protein palmitoylation in schizophrenia is not due to chronic antipsychotic treatment. These results indicate there are changes in the extent of S-palmitoylation of many proteins in the frontal cortex in schizophrenia. Given the roles of this posttranslational modification, these data suggest a potential mechanism reconciling previous observations of abnormal intracellular targeting and trafficking of neurotransmitter receptors in this illness.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0021, USA.
authors.forename: Anita L
authors.initials: AL
authors.lastname: Pinner
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294-0021, USA.
authors.forename: Janusz
authors.initials: J
authors.lastname: Tucholski
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH 45219, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: McCullumsmith
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0021, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Meador-Woodruff
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001923:Brain Chemistry; D005260:Female; D006220:Haloperidol / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D054878:Lipoylation / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D011506:Proteins; D006220:Haloperidol
keywords: Lipid modification; Neurotransmission; Postmortem; S-Palmitoylation; Subcellular localization; Trafficking