title: Evidence revealing deregulation of the KLF11-MAO A pathway in association with chronic stress and depressive disorders.
abstract: The biochemical pathways underlying major depressive disorder (MDD) and chronic stress are not well understood. However, it has been reported that monoamine oxidase A (MAO A, a major neurotransmitter-degrading enzyme) is significantly increased in the brains of human subjects affected with MDD and rats exposed to chronic social defeat (CSD) stress, which is used to model depression. In the current study, we compared the protein levels of a MAO A-transcriptional activator, Kruppel-like factor 11 (KLF11 , also recognized as transforming growth factor-beta-inducible early gene 2) between the brains of 18 human subjects with MDD and 18 control subjects. We found that, indeed, the expression of KLF11 is increased by 36% (p<0.02) in the postmortem prefrontal cortex of human subjects with MDD compared with controls. We also observed a positive correlation between KLF11 levels and those of its target gene, MAO A, both in association with MDD. KLF11 protein expression was also increased by 44% (p<0.02) in the frontal cortex of KLF11 wild-type mice (Klf11(+/+)) vs Klf11(-/-) when both exposed to CSD stress. In contrast, locomotor activities, central box duration and sucrose preference were significantly reduced in the stressed Klf11(+/+) mice, suggesting that Klf11(+/+) mice are more severely affected by the stress model compared with Klf11(-/-) mice. These results serve to assign an important role of KLF11 in upregulating MAO A in MDD and chronic social stress, suggesting that inhibition of the pathways regulated by this transcription factor may aid in the therapeutics of neuropsychiatric illnesses. Thus, the new knowledge derived from the current study extends our understanding of transcriptional mechanisms that are operational in the pathophysiology of common human diseases and thus bears significant biomedical relevance.
authors.affiliation: Department of Psychiatry and Human Behavior, Jackson, MS, USA.
authors.forename: Sharonda
authors.initials: S
authors.lastname: Harris
authors.affiliation: Department of Psychiatry and Human Behavior, Jackson, MS, USA.
authors.forename: Shakevia
authors.initials: S
authors.lastname: Johnson
authors.affiliation: 1] Department of Psychiatry and Human Behavior, Jackson, MS, USA [2] Program in Neuroscience, Jackson, MS, USA.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Duncan
authors.affiliation: Department of Psychiatry and Human Behavior, Jackson, MS, USA.
authors.forename: Chinelo
authors.initials: C
authors.lastname: Udemgba
authors.affiliation: Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Meyer
authors.affiliation: Ottawa Hospital Research Institute (Neuroscience), Ottawa, Ontario, Canada.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Albert
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, GI Research Unit, Mayo Clinic, Rochester, MN, USA.
authors.forename: Gwen
authors.initials: G
authors.lastname: Lomberk
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, GI Research Unit, Mayo Clinic, Rochester, MN, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
authors.affiliation: Department of Psychiatry and Human Behavior, Jackson, MS, USA.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Ou
authors.affiliation: 1] Department of Psychiatry and Human Behavior, Jackson, MS, USA [2] Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stockmeier
authors.affiliation: 1] Department of Psychiatry and Human Behavior, Jackson, MS, USA [2] Program in Neuroscience, Jackson, MS, USA [3] Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Jun Ming
authors.initials: JM
authors.lastname: Wang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000378:metabolism*; D004195:Disease Models, Animal; D004291:Dominance-Subordination; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000378:metabolism*; D009043:Motor Activity / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism*; D012720:Severity of Illness Index; D013315:Stress, Psychological / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C115117:KLF11 protein, human; C506460:KLF11 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human