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Transcription profiling of human dendritic cells from PLOSL patients show abnormalities in pathways of actin bundling and immune response

ABSTRACT: This study was aimed to identify pathways associated with loss-of-function of the DAP12/TREM2 receptor complex and thus gain insight into pathogenesis of PLOSL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy). Transcript profiles of PLOSL patients' DCs showed differential expression of genes involved in actin bundling and immune response, but also for the stability of myelin and bone remodeling. Experiment Overall Design: Transcript profiles of in vitro differentiated DCs of three controls and five PLOSL patients were analyzed.

ORGANISM(S): Homo sapiens

DISEASE(S): Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy

SUBMITTER: Anna Kiialainen

PROVIDER: E-GEOD-3624 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcript profiles of dendritic cells of PLOSL patients link demyelinating CNS disorders with abnormalities in pathways of actin bundling and immune response.

Kiialainen Anna A Veckman Ville V Saharinen Juha J Paloneva Juha J Gentile Massimiliano M Hakola Panu P Hemelsoet Dimitri D Ridha Basil B Kopra Outi O Julkunen Ilkka I Peltonen Leena L

Journal of molecular medicine (Berlin, Germany) 20070526 9

Rare monogenic dementias have repeatedly exposed novel pathways guiding to details of the molecular pathogenesis behind this complex clinical phenotype. In this paper, we have studied polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), an early onset dementia with bone fractures caused by mutations in TYROBP (DAP12) and TREM2 genes, which encode important signaling molecules in human dendritic cells (DCs). To identify the pathways and biological processes associ ...[more]

PMID: 17530208

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Transcript profiles of DCs of PLOSL patients show abnormalities in pathways of actin bundling and immune response

Project description:This study was aimed to identify pathways associated with loss-of-function of the DAP12/TREM2 receptor complex and thus gain insight into pathogenesis of PLOSL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy). Transcript profiles of PLOSL patients' DCs showed differential expression of genes involved in actin bundling and immune response, but also for the stability of myelin and bone remodeling. Keywords: PLOSL patient samples vs. control samples

2007-06-01 | GSE3624 | GEO

Dap12 microglia

Project description:Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is an inherited brain and bone disease. It manifests as dementia and bone fractures. The PLOSL phenotype is caused by loss-of-function mutations in one of the two genes encoding the components of the DAP12/TREM2 receptor complex. The DAP12/TREM2 complex is expressed in cells of the myeloid lineage, including microglia in the central nervous system (CNS). The molecular mechanisms producing the CNS phenotype of PLOSL remain largely unknown. To gain insight into dysfunctional CNS pathways behind PLOSL, we performed genome-wide expression analysis of Dap12 (Tyrobp)-deficient mouse microglial cells. Keywords: knock-out response Transcript profiles of three wild type and three Dap12-deficient primary microglial cultures were analyzed.

2011-08-23 | E-GEOD-9043 | biostudies-arrayexpress

Dap12-deficient mouse brain (1 month)

Project description:Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is an inherited brain and bone disease. It manifests as dementia and bone fractures. The PLOSL phenotype is caused by loss-of-function mutations in one of the two genes encoding the components of the DAP12/TREM2 receptor complex. The DAP12/TREM2 complex is expressed in cells of the myeloid lineage, including microglia in the central nervous system (CNS). The molecular mechanisms producing the CNS phenotype of PLOSL remain largely unknown. To gain insight into dysfunctional CNS pathways behind PLOSL, we performed genome-wide expression analysis of Dap12 (Tyrobp)-deficient mouse brain. In Dap12-deficient mice, we observed alterations in several pathways involved in synaptic function. In agreement with the myelin loss in PLOSL patients, we also saw changes in transcript levels of genes encoding myelin components. Keywords: knockout response Transcript profiles of the midbrain (diencephalon and basal ganglia) of three Dap12-knockout and three heterozygous mice were analyzed.

2011-08-23 | E-GEOD-9061 | biostudies-arrayexpress

Dap12 microglia

2011-08-24 | GSE9043 | GEO

Dap12-deficient mouse brain (1 month)

Project description:Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is an inherited brain and bone disease. It manifests as dementia and bone fractures. The PLOSL phenotype is caused by loss-of-function mutations in one of the two genes encoding the components of the DAP12/TREM2 receptor complex. The DAP12/TREM2 complex is expressed in cells of the myeloid lineage, including microglia in the central nervous system (CNS). The molecular mechanisms producing the CNS phenotype of PLOSL remain largely unknown. To gain insight into dysfunctional CNS pathways behind PLOSL, we performed genome-wide expression analysis of Dap12 (Tyrobp)-deficient mouse brain. In Dap12-deficient mice, we observed alterations in several pathways involved in synaptic function. In agreement with the myelin loss in PLOSL patients, we also saw changes in transcript levels of genes encoding myelin components. Keywords: knockout response

2011-08-24 | GSE9061 | GEO

Gene expression profile of THP-1 monocytes following knockdown of DAP12, a causative gene for Nasu-Hakola disease

2011-11-17 | GSE33500 | GEO

Gene expression profile of DAP12 knockdown THP-1 cells following exposure to phorbol 12-myristate 13-acetate

Project description:Nasu-Hakola disease (NHD), also designated polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a rare autosomal recessive disorder characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by a loss-of-function mutation of DAP12 or TREM2. TREM2 and DAP12 constitute a receptor/adaptor complex expressed on osteoclasts, dendritic cells, macrophages, monocytes, and microglia. At present, the precise molecular mechanisms underlying development of leukoencephalopathy and bone cysts in NHD remain largely unknown. We established THP-1 human monocyte clones that stably express small interfering RNA (siRNA) targeting DAP12 for serving as a cellular model of NHD. Genome-wide transcriptome analysis identified a set of 22 genes consistently downregulated in DAP12 knockdown cells. They constituted the molecular network closely related to the network defined by cell-to-cell signaling and interaction, hematological system development and function, and inflammatory response, where NF-kappaB acts as a central regulator. These results suggest that a molecular defect of DAP12 in human monocytes deregulates the gene network pivotal for maintenance of myeloid cell function in NHD. We found that both DAP12 knockdown and control clones were capable of equally responding to phorbol 12-myristate 13-acetate (PMA), a known inducer of morphological differentiation of THP-1 cells, by exhibiting almost similar gene expression profiles between both, following a 24-hour exposure to 50 nM PMA.

2011-11-17 | GSE33503 | GEO

Gene expression profile of THP-1 monocytes following knockdown of DAP12, a causative gene for Nasu-Hakola disease

Project description:Nasu-Hakola disease (NHD), also designated polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a rare autosomal recessive disorder characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by a loss-of-function mutation of DAP12 or TREM2. TREM2 and DAP12 constitute a receptor/adaptor complex expressed on osteoclasts, dendritic cells, macrophages, monocytes, and microglia. At present, the precise molecular mechanisms underlying development of leukoencephalopathy and bone cysts in NHD remain largely unknown. We established THP-1 human monocyte clones that stably express small interfering RNA (siRNA) targeting DAP12 for serving as a cellular model of NHD. Genome-wide transcriptome analysis identified a set of 22 genes consistently downregulated in DAP12 knockdown cells. They constituted the molecular network closely related to the network defined by cell-to-cell signaling and interaction, hematological system development and function, and inflammatory response, where NF-kappaB acts as a central regulator. These results suggest that a molecular defect of DAP12 in human monocytes deregulates the gene network pivotal for maintenance of myeloid cell function in NHD. The siRNA vector construct targeting the DAP12 sequence (SI) and the control vector construct targeting the scrambled sequence (SCR) were generated by using GeneClip U1 Hairpin cloning system (Promega). The vectors were transfected in THP-1 cells by using Lipofectamine LTX reagent. The stable cell lines were selected by incubating them for approximately two months in the feeding medium with inclusion of 200 microgram/ml Hygromycin B. Then, two SI clones named SI5 and SI17, in addition to two SCR clones named SCR1 and SCR4, were selected by limiting dilution of the cells in a manner of a single cell per well plated in a 96-well cell culture plate.

2011-11-17 | E-GEOD-33500 | biostudies-arrayexpress

Transcriptome analysis of the Nasu-Hakola disease brain

Project description:Nasu-Hakola disease (NHD), also designated polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; OMIM 221770), is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of DAP12 and TREM2, which constitute a receptor/adapter signaling complex expressed on osteoclasts, dendritic cells, macrophages, and microglia. No Japanese patients with TREM2 mutations have been reported previously. We reported three siblings affected with NHD in a Japanese family. Among them, two died of NHD during the fourth decade of life. The transcriptome was studied in the autopsized brain of one patient. We found a homozygous conversion of a single nucleotide T to C at the second position of intron 3 in the splice-donor consensus site (c.482+2T>C) of the TREM2 gene, resulting in exon 3 skipping. We identified 136 upregulated genes involved in inflammatory response and immune cell trafficking and 188 downregulated genes including a battery of GABA receptor subunits and synaptic proteins in the patient’s brain.

2010-11-20 | GSE25496 | GEO

Transcriptome analysis of the Nasu-Hakola disease brain

2010-11-20 | E-GEOD-25496 | biostudies-arrayexpress