GFAP canonical transcript may not be suitable for the diagnosis of adult-onset Alexander disease

Vairo, Filippo Pinto e; Bertsch, Nicole L.; Klee, Eric W.; Gavrilova, Ralitza H.

doi:10.1186/s40478-018-0616-z

Cited by 4 publications

(2 citation statements)

References 3 publications

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“…Besides, some studies have found that the number of astrocytes in the brain and the expression of its specific cytoskeleton protein Glial Fibrillary Acidic Protein (GFAP) are significantly decreased in some young patients with early-onset depression, and the expression level of GFAP can increase with age (10). GFAP is a biological marker protein of astrocytes (11). Numerous studies have shown that GFAP is involved in various physiological functions of astrocyte, such as maintaining the blood-brain barrier, synaptic plasticity, cell proliferation, and regulating the transport of vesicles and lysosomes in astrocyte (12).…”

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confidence: 99%

Effects of Xiaoyaosan on Depressive-Like Behaviors in Rats With Chronic Unpredictable Mild Stress Through HPA Axis Induced Astrocytic Activities

Song

Zhang

et al. 2020

Front. Psychiatry

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Astrocytes in the hippocampus are immediately relevant to depressive-like behavior. By regulating their activities, Xiaoyaosan (XYS), a traditional Chinese medicine compound, works in the treatment of depression.Objective: Chronic unpredictable mild stress (CUMS) rat model was established to observe the regulation of XYS. We investigated the behavioral changes of CUMS, the expression of corticosterone (CORT) of the hypothalamo-pituitary-adrenal (HPA) axis, the expression of Glu-NMDA receptor and astrocytes glial fibrillary acidic protein (GFAP) in the hippocampus. We also investigated whether these changes were linked to XYS.Methods: 80 adult SD rats were randomly divided into four groups, control group, CUMS group, XYS group, and fluoxetine group. The rats in the control group and the CUMS group received 0.5 ml of deionized water once a day by intragastrically administration. Rats in the two treatment groups received XYS (2.224g/kg/d) and fluoxetine (2.0mg/kg/d) once a day, respectively. Rat hippocampus GFAP and Glu-NMDA receptor were respectively detected by real-time fluorescent quantitative PCR and western blot. The CORT of HPA axis was detected by Elisa. Body weight, food intake, and behavioral tests, such as open field tests, the sucrose preference test, and exhaustive swimming test, were used to assess depressive-like behavior in rats.Results: In this work, significant behavioral changes and differences in expression of the CORT of HPA axis and hippocampal GFAP and Glu-NMDA receptor were presented in CUMS-exposed rats. Like fluoxetine, XYS improved CUMS-induced rat's body weight, food intake, and depressive-like behavior. The study also proved that XYS could reverse the CUMS-induced changes of the CORT of HPA axis and affect the astrocytic activities and down-regulate the NR2B subunit of NMDA receptor (NR2B) level in the hippocampus.

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Section: Introductionmentioning

confidence: 99%

Effects of Xiaoyaosan on Depressive-Like Behaviors in Rats With Chronic Unpredictable Mild Stress Through HPA Axis Induced Astrocytic Activities

Song

Zhang

et al. 2020

Front. Psychiatry

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“…The c.1289G>A variant has been previously described in several cases; a sibling pair 81 with adult-onset AxD [11], and two descriptions of single, unrelated individuals in Karp 82 et al and Pinto e Vairo et al [9,13] (Table 1). It is possible that the patient reported by 83 Pinto e Vairo et al (2018) is related to the individuals we have studied in Family 1, and 84 hence not an independent occurrence of this variant [13]. In the study by Melchionda et 85 al., it was hypothesized that the pathogenic effect of the c.1289G>A variant resulted 86 from perturbation of the GFAP network by inefficiently incorporated GFAP-Arg430His 87 protein [11].…”

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confidence: 96%

Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform

Helman

Takanohashi

Hagemann

et al. 2019

Preprint

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Alexander disease results from gain of function mutations in the gene encoding glial fibrillary acidic protein (GFAP), an intermediate filament protein expressed in astrocytes. At least eight GFAP isoforms have been described, however, the predominant alpha isoform accounts for approximately 90% of GFAP protein in the central nervous system. Here we describe exonic variants identified in three unrelated families with Type II Alexander disease that alter the splicing of GFAP pre-mRNA and result in upregulation of a previously uncharacterized GFAP lambda isoform (NM 001363846.1). Affected members of Family 1 and Family 2 shared the same missense variant, NM 001363846.1:c.1289G>A;p.(Arg430His) while in Family 3 we identified a synonymous variant in the adjacent nucleotide, NM 001363846.1:c.1290C>A;p.(Arg430Arg). Using RNA and protein analysis of brain autopsy samples, and a mini-gene splicing reporter assay, we demonstrate both variants result in upregulation of the lambda isoform. We assessed other GFAP variants in the ClinVar database for predicted aberrant splicing and using the same assay demonstrated significant changes to splicing for two selected variants. Our approach demonstrates the importance of characterizing the effect of GFAP variants on mRNA splicing in order to inform future pathophysiologic and therapeutic study for Alexander disease.

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Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform

et al. 2020

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GFAP canonical transcript may not be suitable for the diagnosis of adult-onset Alexander disease

Cited by 4 publications

References 3 publications

Effects of Xiaoyaosan on Depressive-Like Behaviors in Rats With Chronic Unpredictable Mild Stress Through HPA Axis Induced Astrocytic Activities

Effects of Xiaoyaosan on Depressive-Like Behaviors in Rats With Chronic Unpredictable Mild Stress Through HPA Axis Induced Astrocytic Activities

Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform

Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform

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