Original Article

Journal of Molecular Medicine

, Volume 85, Issue 9, pp 971-983

First online:

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

  • Anna KiialainenAffiliated withDepartment of Molecular Medicine, National Public Health Institute
  • , Ville VeckmanAffiliated withDepartment of Viral Diseases and Immunology, National Public Health Institute
  • , Juha SaharinenAffiliated withDepartment of Molecular Medicine, National Public Health InstituteBiomedicum Bioinformatics Unit, University of Helsinki
  • , Juha PalonevaAffiliated withDepartment of Molecular Medicine, National Public Health Institute
  • , Massimiliano GentileAffiliated withBiomedicum Bioinformatics Unit, University of Helsinki
  • , Panu HakolaAffiliated withDepartment of Forensic Psychiatry, University of Kuopio
  • , Dimitri HemelsoetAffiliated withDepartment of Neurology, Ghent University Hospital
  • , Basil RidhaAffiliated withDementia Research Centre, National Hospital for Neurology and Neurosurgery
  • , Outi KopraAffiliated withDepartment of Molecular Medicine, National Public Health InstituteNeuroscience Center, University of Helsinki
    • , Ilkka JulkunenAffiliated withDepartment of Viral Diseases and Immunology, National Public Health Institute
    • , Leena PeltonenAffiliated withDepartment of Molecular Medicine, National Public Health InstituteDepartment of Medical Genetics, University of HelsinkiThe Broad Institute, MIT Email author 

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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.

Keywords

DAP12 TREM2 Nasu–Hakola disease Dendritic cells Human