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C-Jun N-terminal kinase controls a negative loop in the regulation of glial fibrillary acidic protein expression by retinoic acid.

ABSTRACT: Glial fibrillary acidic protein (GFAP) is a protein widely used as a molecular marker for astroglial differentiation and mature astrocytes. We and others have shown previously that retinoic acid and specific cytokines induce the expression of GFAP in neural precursor cells by activating the phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K) phosphorylation pathway. Here, we extend our previous work and show that retinoic acid also activates specifically the c-Jun N-terminal kinase (JNK) phosphorylation pathway, which in turn inhibits GFAP expression. Our results suggest the existence of a negative self-regulatory loop in the phosphorylation pathways that regulates GFAP expression. This loop is constitutively repressed by the PI3K pathway. Our results could be relevant for disorders involving sustained GFAP overexpression in precursor cells, such as glioblastoma and Alexander disease.

SUBMITTER: Herrera F

PROVIDER: S-EPMC4539028 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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c-Jun N-terminal kinase controls a negative loop in the regulation of glial fibrillary acidic protein expression by retinoic acid.

Herrera F F Maher P P Schubert D D

Neuroscience 20120215

Glial fibrillary acidic protein (GFAP) is a protein widely used as a molecular marker for astroglial differentiation and mature astrocytes. We and others have shown previously that retinoic acid and specific cytokines induce the expression of GFAP in neural precursor cells by activating the phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K) phosphorylation pathway. Here, we extend our previous work and show that retinoic acid also activates specifically the c-Jun N-terminal kinase (JNK) phosp ...[more]

PMID: 22387108

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Project description:IntroductionThere is a tremendous need for identifying reliable blood-based biomarkers for Alzheimer's disease (AD) that are tied to the biological ATN (amyloid, tau and neurodegeneration) framework as well as clinical assessment and progression.MethodsOne hundred forty-four elderly participants underwent 18F-AV45 positron emission tomography (PET) scan, structural magnetic resonance imaging (MRI) scan, and blood sample collection. The composite standardized uptake value ratio (SUVR) was derived from 18F-AV45 PET to assess brain amyloid burden, and the hippocampal volume was determined from structural MRI scans. Plasma glial fibrillary acidic protein (GFAP), phosphorylated tau-181 (ptau-181), and neurofilament light (NfL) measured by single molecular array (SIMOA) technology were assessed with respect to ATN framework, genetic risk factor, age, clinical assessment, and future functional decline among the participants.ResultsAmong the three plasma markers, GFAP best discriminated participants stratified by clinical diagnosis and brain amyloid status. Age was strongly associated with NfL, followed by GFAP and ptau-181 at much weaker extent. Brain amyloid was strongly associated with plasma GFAP and ptau-181 and to a lesser extent with plasma NfL. Moderate association was observed between plasma markers. Hippocampal volume was weakly associated with all three markers. Elevated GFAP and ptau-181 were associated with worse cognition, and plasma GFAP was the most predictive of future functional decline. Combining GFAP and ptau-181 together was the best model to predict brain amyloid status across all participants (AUC = 0.86) or within cognitively impaired participants (AUC = 0.93); adding NfL as an additional predictor only had a marginal improvement.ConclusionOur findings indicate that GFAP is of potential clinical utility in screening amyloid pathology and predicting future cognitive decline. GFAP, NfL, and ptau-181 were moderately associated with each other, with discrepant relevance to age, sex, and AD genetic risk, suggesting their relevant but differential roles for AD assessment. The combination of GFAP with ptau-181 provides an accurate model to predict brain amyloid status, with the superior performance of GFAP over ptau-181 when the prediction is limited to cognitively impaired participants.

Dataset Information

C-Jun N-terminal kinase controls a negative loop in the regulation of glial fibrillary acidic protein expression by retinoic acid.

Publications

c-Jun N-terminal kinase controls a negative loop in the regulation of glial fibrillary acidic protein expression by retinoic acid.

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