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Insensitivity of PI3K/Akt/GSK3 signaling in peripheral blood mononuclear cells of age-related macular degeneration patients.

ABSTRACT: Our recent studies with cultured retinal pigment epithelium cells suggested that overexpression of interleukin 17 receptor C (IL-17RC), a phenomenon observed in peripheral blood and chorioretinal tissues with age-related macular degeneration (AMD), was associated with altered activation of phosphatidylinositide 3-kinase (PI3K), Akt, and glycogen synthase kinase 3 (GSK3). We wondered whether or not altered PI3K, Akt, and GSK3 activities could be detected in peripheral blood mononuclear cells (PBMC) obtained from AMD patients. In the patients' PBMC, absent or reduced serine-phosphorylation of GSK3α or GSK3β was observed, which was accompanied with increased phosphorylation of GSK3 substrates (e.g. CCAAT enhancer binding protein α, insulin receptor substrate 1, and TAU), indicative of enhanced GSK3 activation. In addition, decreased protein mass of PI3K85α and tyrosine-phosphorylation of PI3K50α was present in PBMC of the AMD patients, suggesting impaired PI3K activation. Moreover, abnormally lowered molecular weight forms of Akt and GSK3 were detected in PBMC of the AMD patients. These data demonstrate that despite the presence of high levels of IL-17RC, Wnt-3a and vascular endothelial growth factor, the PI3K/Akt/GSK3 signaling pathway is insensitive to these stimuli in PBMC of the AMD patients. Thus, measurement of PI3K/Akt/GSK3 expression and activity in PBMC may serve as a surrogate biomarker for AMD.

SUBMITTER: Liu X

PROVIDER: S-EPMC5460613 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Project description:BackgroundAge-related macular degeneration (AMD) is the leading cause of severe vision loss in patients over 55 years old in the industrialized world. In the past 20 years, approximately 288 million patents have been affected by this disease. Despite this high prevalence, the molecular mechanism for AMD remains unclear, and there remains no effective treatment for this disease. The mosaic loss of Y chromosome (mLOY) has been identified as a common phenomenon in multiple age-related disease (i.e., oncogenesis and cardiovascular disease) has recently been identified by genome-wide analysis to be linked to AMD as well. As the Y chromosome mainly possesses three genomic functions, sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling, here we characterize the Y chromosome euchromatic genes and non-chromosome AMD genes in relevance to cellular proliferation and apoptotic signaling of leukocytes.ResultsUsing STRING, a publically available database of all protein-protein interaction, Grassmann et al. found the genes on the Y chromosome is mainly believed to take part in three major cellular genomic functions- sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling. Based on data from the Ensembl Genome database, we focus on our discussion on coding genes found in the euchromatins but not the PAR1 and PAR2 regions of the Y chromosomes. All 14 known euchromatic genes on the Y chromosome short arm and all 31 known euchromatic genes on the Y chromosome long arm (Yq) are directly or indirectly involved in the cell cycle (meiosis and mitosis) and proliferation. We sorted non-Y chromosome AMD associated genes into these three categories to identify signaling pathways that may compound with cellular dysregulation due to mLOY. Of the genes associated with AMD, complement pathway genes such as C2, C9 and CFH/ARMD4 are associated with proliferation, receptor-mediated endocytosis genes such as APOE, DAB2 and others associated with apoptotic signaling. Because nucleated cells found in peripheral circulation are mainly composed of leukocytes with reduced expression of CD99, a protein essential for leukocytes adhesion, translocation, and function, mLOY in these cells likely affect retinal degeneration through altered immunological surveillance. In fact, there is precedence that circulating macrophage can stabilize and modify the cardiac rhythm and contractility post ischemic damage. Therefore, the most likely mechanism through which peripheral mLOY affects AMD development in men is through the role affected leukocytes play in retinal proliferation and apoptosis.ConclusionsmLOY in peripheral blood is newly discovered in AMD by Grassmann et al. as it is a common phenomenon in oncogenesis and cardiac dysfunction. Here the recent data conclude the possible mechanism for the newly identified link between mLOY and AMD, and provide support that mLOY in circulating macrophage-monocyte of affected male patients promotes AMD by targeting the retina and causing macular degeneration.

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Insensitivity of PI3K/Akt/GSK3 signaling in peripheral blood mononuclear cells of age-related macular degeneration patients.

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