Journal of Molecular Medicine

, Volume 85, Issue 9, pp 971–983

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

Authors

  • Anna Kiialainen
    • Department of Molecular MedicineNational Public Health Institute
  • Ville Veckman
    • Department of Viral Diseases and ImmunologyNational Public Health Institute
  • Juha Saharinen
    • Department of Molecular MedicineNational Public Health Institute
    • Biomedicum Bioinformatics UnitUniversity of Helsinki
  • Juha Paloneva
    • Department of Molecular MedicineNational Public Health Institute
  • Massimiliano Gentile
    • Biomedicum Bioinformatics UnitUniversity of Helsinki
  • Panu Hakola
    • Department of Forensic PsychiatryUniversity of Kuopio
  • Dimitri Hemelsoet
    • Department of NeurologyGhent University Hospital
  • Basil Ridha
    • Dementia Research CentreNational Hospital for Neurology and Neurosurgery
  • Outi Kopra
    • Department of Molecular MedicineNational Public Health Institute
    • Neuroscience CenterUniversity of Helsinki
  • Ilkka Julkunen
    • Department of Viral Diseases and ImmunologyNational Public Health Institute
    • Department of Molecular MedicineNational Public Health Institute
    • Department of Medical GeneticsUniversity of Helsinki
    • The Broad InstituteMIT
Original Article

DOI: 10.1007/s00109-007-0191-4

Cite this article as:
Kiialainen, A., Veckman, V., Saharinen, J. et al. J Mol Med (2007) 85: 971. doi:10.1007/s00109-007-0191-4

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

DAP12TREM2Nasu–Hakola diseaseDendritic cellsHuman

Copyright information

© Springer-Verlag 2007