title: Abnormalities of the Duo/Ras-related C3 botulinum toxin substrate 1/p21-activated kinase 1 pathway drive myosin light chain phosphorylation in frontal cortex in schizophrenia.
abstract: BACKGROUND
  Recent studies on GTPases have suggested that reduced Duo and cell division cycle 42 (Cdc42) transcript expression is involved in dendritic spine loss in schizophrenia. In murine models, Duo and Cdc42 phosphorylate p21-activated kinase 1 (PAK1), which modifies the activity of regulatory myosin light chain (MLC) and cofilin by altering their phosphorylation. Therefore, we hypothesized that in schizophrenia abnormal Duo and Cdc42 expression result in changes in MLC and/or cofilin phosphorylation, which might alter actin cytoskeleton dynamics underlying dendritic spine maintenance.
  
  
  METHODS
  We performed Western blot protein expression analysis in postmortem brains from patients diagnosed with schizophrenia and a comparison group. We focused our studies in the anterior cingulate cortex (ACC; n = 33 comparison group; n = 36 schizophrenia) and dorsolateral prefrontal cortex (DLPFC; n = 29 comparison group; n = 35 schizophrenia).
  
  
  RESULTS
  In both ACC and DLPFC, we found a reduction of Duo expression and PAK1 phosphorylation in schizophrenia. Cdc42 protein expression was decreased in ACC but not in DLPFC. In ACC, we observed decreased PAK1 phosphorylation and increased MLC phosphorylation (pMLC), whereas in DLPFC pMLC remained unchanged.
  
  
  CONCLUSIONS
  These data suggest a novel mechanism that might underlie dendritic spine loss in schizophrenia. The increase in pMLC seen in ACC might be associated with dendritic spine shrinkage. The lack of an effect on pMLC in DLPFC suggests that in schizophrenia PAK1 downstream pathways are differentially affected in these cortical areas.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0021, USA. mrubio@uab.edu
authors.forename: María D
authors.initials: MD
authors.lastname: Rubio
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; D003599:Cytoskeleton / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006179:Gyrus Cinguli / Q000378:metabolism*; D006801:Humans; D008297:Male; D018994:Myosin Light Chains / Q000378:metabolism*; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D064067:Rho Guanine Nucleotide Exchange Factors; D012559:Schizophrenia / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D018994:Myosin Light Chains; D064067:Rho Guanine Nucleotide Exchange Factors; C503866:KALRN protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein