Objective: To evaluate a cell type specific action of DJ-1, a PD and cancer associated gene, in intracellular signaling pathways.

Background: Understanding the pathophysiology of Parkinson’s disease (PD) has highly profited from the elucidation of the molecular mechanisms implicated in genetic PD using a variety of different model systems. However, PD associated genes are expressed ubiquitously and thus might modulate in different somatic cell types distinct intracellular signaling pathways. In view of potential therapeutic interventions associated with gene function, it is of importance to understand the complex and cell type specific action of these genes in order to appropriately address possible side effects.

Methods: We analyzed different intracellular signaling pathways (NFkb, ERK (p42/44), and p38) in different immortalized mouse embryonic fibroblast cell lines (MEFs) and primary microglia derived from DJ-1 deficient mice at baseline conditions and after LPS stimulation using quantitative Western blot analysis. Both cell types are known to express DJ-1 and the former has been extensively studied for elucidation of DJ-1 effects on the intracellular signaling cascades. The effect of DJ-1 onto intracellular signaling in microglia is, however, not yet known.

Results: We found that DJ-1 is necessary to activate the NFκb signaling cascade upstream of IKKακ in immortalized DJ-1 deficient MEFs, thereby supporting the findings of McNally et al (2011) showing that DJ-1 interacts with Cezanne, an upstream regulator of NFκb signaling. In addition we showed that in MEFs DJ-1 is also necessary to activate the p38 signaling pathway but not the ERK1/2 pathway. However, in primary microglia DJ-1 deficiency does not lead to an abolishment of the NFκb signaling, which is supported by the finding that NFκb dependent cytokine release in DJ-1 deficient microglia is also not affected up to 24 hrs after LPS stimulation. Again the ERK1/2 signaling pathway in this cell type is not affected by the absence of DJ-1.

Conclusions: DJ-1, a PD associated gene ubiquitously expressed in different somatic cell types, exerts in different somatic cell types distinct functions in respect to modulating intracellular signaling pathways. In particular, while DJ-1 is necessary for the activation of NFκ signaling in MEFs, it is dispensable for the modulation of this pathway in primary microglia, the major cell type involved in neuroinflammatory responses in the brain.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dj-1-regulates-intracellular-signaling-in-a-highly-cell-type-specific-manner/