ABSTRACT
BACKGROUND: Expression of the neuronal membrane glycoprotein M6a (GPM6A), the proteolipid protein (PLP/DM20) family member, is downregulated in the hippocampus of chronically stressed animals. Its neuroplastic function involves a role in neurite formation, filopodium outgrowth and synaptogenesis through an unknown mechanism. Disruptions in neuroplasticity mechanisms have been shown to play a significant part in the etiology of depression. Thus, the current investigation examined whether GPM6A expression is also altered in human depressed brain. METHODS: Expression levels and coexpression patterns of GPM6A, GPM6B, and PLP1 (two other members of PLP/DM20 family) as well as of the neuroplasticity-related genes identified to associate with GPM6A were determined using quantitative polymerase chain reaction (qPCR) in postmortem samples from the hippocampus (n = 18) and the prefrontal cortex (PFC) (n = 25) of depressed suicide victims and compared with control subjects (hippocampus n = 18; PFC n = 25). Neuroplasticity-related proteins that form complexes with GPM6A were identified by coimmunoprecipitation technique followed by mass spectrometry. RESULTS: Results indicated transcriptional downregulation of GPM6A and GPM6B in the hippocampus of depressed suicides. The expression level of calcium/calmodulin-dependent protein kinase II alpha (CAMK2A) and coronin1A (CORO1A) was also significantly decreased. Subsequent analysis of coexpression patterns demonstrated coordinated gene expression in the hippocampus and in the PFC indicating that the function of these genes might be coregulated in the human brain. However, in the brain of depressed suicides this coordinated response was disrupted. CONCLUSIONS: Disruption of coordinated gene expression as well as abnormalities in GPM6A and GPM6B expression and expression of the components of GPM6A complexes were detected in the brain of depressed suicides.
Subject(s)
Depressive Disorder, Major/metabolism , Gene Expression , Hippocampus/metabolism , Neuronal Plasticity/genetics , Prefrontal Cortex/metabolism , Suicide , Adaptor Proteins, Signal Transducing/metabolism , Adult , Aged , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cell Cycle Proteins/metabolism , Depressive Disorder, Major/genetics , Female , Humans , Male , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Microfilament Proteins/metabolism , Middle Aged , Myelin Proteolipid Protein/genetics , Myelin Proteolipid Protein/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Young AdultABSTRACT
Nuclear DNA helicase II (NDH II) is a member of the DEAH superfamily of helicases and functions as a pre-mRNA- and mRNA-binding protein in human cells. Here we report for the first time that human NDH II is associated with the nucleolus of transformed and nontransformed cells as shown by immunofluorescence and by ultrastructural studies. When RNA polymerase II (POL II) transcription is inhibited, NDH II highly accumulates in the nucleolus and shows predominant association with subdomains in DFC and in a portion of GC attached to DFC. Furthermore, these subdomains completely co-localize with mRNA-binding protein TLS. In addition, we show that nucleolar accumulation of NDH II is closely related to G(0)-phase growth arrest in human fibroblasts. Thus, the nucleolar localization of NDH II depends upon the metabolic state of the cell. Based on the data we propose that NDH II operates in both nucleoplasmic and nucleolar mode, and that its redistribution reflects accumulations indicating a possible cycling of NDH II between nucleoplasm and the nucleolus. The nucleolus can serve as a temporary storage or recycling center for NDH II. Possible functions of NDH II in pre-rRNA biogenesis, or in nucleolar mRNA metabolism, are also discussed.
