title: Transcript profiles of dendritic cells of PLOSL patients link demyelinating CNS disorders with abnormalities in pathways of actin bundling and immune response.
abstract: 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 associated with DAP12/TREM2-mediated signaling, we performed genome wide transcript analysis of in vitro differentiated DCs of PLOSL patients representing functional knockouts of either DAP12 or TREM2. Both DAP12- and TREM2-deficient cells differentiated into DCs and responded to pathogenic stimuli. However, the DCs showed morphological differences compared to control cells due to defects in the actin filaments. Not unexpectedly, transcript profiles of the patient DCs showed differential expression of genes involved in immune response. Importantly, significantly diverging transcript levels were also evident for genes earlier associated with other disorders of the central nervous system (CNS) and genes involved in the remodeling of bone, linking these two immunological genes with critical tissue phenotypes of patients. The data underline the functional diversity of the molecules of the innate immune system and implies their significant contribution also in demyelinating CNS disorders, including those resulting in dementia.
authors.affiliation: Department of Molecular Medicine, National Public Health Institute, Biomedicum, Haartmaninkatu 8, 00290, Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kiialainen
authors.forename: Ville
authors.initials: V
authors.lastname: Veckman
authors.forename: Juha
authors.initials: J
authors.lastname: Saharinen
authors.forename: Juha
authors.initials: J
authors.lastname: Paloneva
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Gentile
authors.forename: Panu
authors.initials: P
authors.lastname: Hakola
authors.forename: Dimitri
authors.initials: D
authors.lastname: Hemelsoet
authors.forename: Basil
authors.initials: B
authors.lastname: Ridha
authors.forename: Outi
authors.initials: O
authors.lastname: Kopra
authors.forename: Ilkka
authors.initials: I
authors.lastname: Julkunen
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000235:genetics; D002493:Central Nervous System Diseases / Q000097:blood / Q000235:genetics*; D003599:Cytoskeleton / Q000378:metabolism; D003711:Demyelinating Diseases / Q000097:blood / Q000235:genetics*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D018613:Microscopy, Confocal; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D010009:Osteochondrodysplasias / Q000097:blood / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; C110546:TYROBP protein, human