title: Alterations of the myristoylated, alanine-rich C kinase substrate (MARCKS) in prefrontal cortex in schizophrenia.
abstract: Abnormal synaptic plasticity has been implicated in the cognitive deficits seen in schizophrenia, where alterations have been found in neurotransmission, signaling and dendritic dynamics. Rapid rearrangement of the actin cytoskeleton is critical for plasticity and abnormalities of molecular regulators of this process are candidates for understanding mechanisms underlying these changes in schizophrenia. The myristoylated, alanine-rich C-kinase substrate (MARCKS) is crucial for many roles associated with synaptic plasticity, including facilitation of neurotransmission, dendritic branching and in turn cognitive function. Accordingly, we hypothesized that this protein is abnormally expressed or regulated in schizophrenia. We measured protein expression of MARCKS by Western blot analysis in postmortem samples of dorsolateral prefrontal cortex (DLPFC) from elderly schizophrenia patients (N=16) and a comparison group (N=20). We also assayed phosphorylated-MARCKS (pMARCKS), given the role of phosphorylation in reversing membrane association by MARCKS. We found decreased expression of both MARCKS and pMARCKS in schizophrenia. Altered myristoylation may be a mechanism that explains this down-regulation of MARCKS, so we also assayed expression of the two isoforms of the key myristoylation enzyme, NMT, and an enzymatic inhibitor of this enzyme, NMT-inhibitor protein (NIP71) by Western blotting in these same subjects. Expression did not change between groups for these proteins, suggesting a mechanism other than myristoylation is responsible for decreased MARCKS expression in schizophrenia. These data suggest a potential mechanism underlying aspects of altered synaptic plasticity observed in schizophrenia.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: apinner@uab.edu.
authors.forename: Anita L
authors.initials: AL
authors.lastname: Pinner
authors.affiliation: Department of Psychiatry, Mt. Sinai School of Medicine, New York, NY, USA.
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Meador-Woodruff
mesh_terms: D000368:Aged; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D015153:Blotting, Western; D015536:Down-Regulation; D005260:Female; D006220:Haloperidol / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007536:Isomerism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; C000619712:Marcks protein, rat; D008565:Membrane Proteins; C492718:N-myristoyltransferase inhibitor protein 71, human; D009363:Neoplasm Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C033563:haloperidol decanoate; D006220:Haloperidol
keywords: Cytoskeleton; Dendritic dynamics; Myristoylation; Neurotransmission; Synaptic plasticity