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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

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Kiialainen, Anna Veckman, Ville Saharinen, Juha Paloneva, Juha Gentile, Massimiliano Peltonen, Leena

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.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2007
Language Anglais
Journal information "Journal of Molecular Medicine" - Vol. 85, no. 9, p. 971-983 (2007)
Peer reviewed yes
Publisher Springer (New York)
issn 0946-2716
e-issn 1432-1440
Publication status Publié
Affiliation UCL
Keywords DAP12 ; TREM2 ; nasu-hakola disease ; dendritic cells ; human
Links
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Bibliographic reference Kiialainen, Anna ; Veckman, Ville ; Saharinen, Juha ; Paloneva, Juha ; Gentile, Massimiliano ; et. al. Transcript profiles of dendritic cells of PLOSL patients link demyelinating CNS disorders with abnormalities in pathways of actin bundling and immune response. In: Journal of Molecular Medicine, Vol. 85, no. 9, p. 971-983 (2007)
Permanent URL http://hdl.handle.net/2078.1/37382