Glial Dysfunction in MeCP2 Deficiency Models: Implications for Rett Syndrome

Kahanovitch, Uri; Patterson, Kelsey; Hernandez, Raymundo; Olsen, Michelle L.

doi:10.3390/ijms20153813

Cited by 34 publications

(29 citation statements)

References 145 publications

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“…In the absence of obvious change in the MBP and without labelling with an astrocyte nuclear marker, it is not fully clear whether the astrocyte number or the GFAP production is reduced. Regardless, these data support prior studies, mainly in animal models, by suggesting an important role for glial dysfunction in human RTT brain [70‐73].…”

Section: Discussionsupporting

confidence: 87%

Differential brain region‐specific expression of MeCP2 and BDNF in Rett Syndrome patients: a distinct grey‐white matter variation

Pejhan

Siu

Ang

et al. 2020

Neuropathology Appl Neurobio

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Introduction and objectives Rett Syndrome (RTT) is a neurodevelopmental disorder caused by Methyl CpG Binding Protein 2 (MECP2) gene mutations. Previous studies of MeCP2 in the human brain showed variable and inconsistent mosaic‐pattern immunolabelling, which has been interpreted as a reflection of activation‐state variability. We aimed to study post mortem MeCP2 and BDNF (MeCP2 target) degradation and brain region‐specific detection in relation to RTT pathophysiology. Methods We investigated MeCP2 and BDNF stabilities in non‐RTT human brains by immunohistochemical labelling and compared them in three brain regions of RTT and controls. Results In surgically excised samples of human hippocampus and cerebellum, MeCP2 was universally detected. There was no significantly obvious difference between males and females. However, post mortem delay in autopsy samples had substantial influence on MeCP2 detection. Immunohistochemistry studies in RTT patients showed lower MeCP2 detection in glial cells of the white matter. Glial fibrillary acidic protein (GFAP) expression was also reduced in RTT brain samples without obvious change in myelin basic protein (MBP). Neurons did not show any noticeable decrease in MeCP2 detection. BDNF immunohistochemical detection showed an astroglial/endothelial pattern without noticeable difference between RTT and controls. Conclusions Our findings indicate that MeCP2 protein is widely expressed in mature human brain cells at all ages. However, our data points towards a possible white matter abnormality in RTT and highlights the importance of studying human RTT brain tissues in parallel with research on animal and cell models of RTT.

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Section: Discussionsupporting

confidence: 87%

Differential brain region‐specific expression of MeCP2 and BDNF in Rett Syndrome patients: a distinct grey‐white matter variation

Pejhan

Siu

Ang

et al. 2020

Neuropathology Appl Neurobio

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“…These represent interesting evidence for differential regulation of MECP2 isoforms between cell types in a sex-specific fashion and support DNA methylation as a prevalent mechanism for the differential regulation. Also, although MECP2 is expressed at much lower levels in astrocytes relative to neurons, it has been reported that MECP2 -null astrocytes negatively affect neurons in a non-cell-autonomous fashion ( 67 , 68 ). The mechanisms regulating MECP2 expression in astrocytes are likely to be relevant for RTT and warrant further research.…”

Section: Mechanistic Insights Into Differential Gene Regulation Of Mementioning

confidence: 99%

Regulation, diversity and function of MECP2 exon and 3′UTR isoforms

Rodrigues

Mufteev

Ellis

2020

Human Molecular Genetics

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The methyl-CpG binding protein 2 (MECP2) is a critical global regulator of gene expression. Mutations in MECP2 cause neurodevelopmental disorders including Rett syndrome (RTT). MECP2 exon 2 is spliced into two alternative mRNA isoforms encoding MECP2-E1 or MECP2-E2 protein isoforms that differ in their N-termini. MECP2-E2, isolated first was used to define the general roles of MECP2 in methyl-DNA binding, targeting of transcriptional regulatory complexes and its disease-causing impact in RTT. It was later found that MECP2-E1 is the most abundant isoform in the brain and its exon 1 is also mutated in RTT. MECP2 transcripts undergo alternative polyadenylation generating mRNAs with four possible 3′UTR lengths ranging from 130 to 8600 nucleotides. Together, the exon and 3′UTR isoforms display remarkable abundance disparity across cell types and tissues during development. These findings indicate discrete means of regulation, and suggest that protein isoforms perform non-overlapping roles. Multiple regulatory programs have been explored to explain these disparities. DNA methylation patterns of the MECP2 promoter and first intron impact MECP2-E1 and E2 isoform levels. Networks of microRNAs and RNA-binding proteins also post-transcriptionally regulate the stability and translation efficiency of MECP2 3′UTR isoforms. Finally, distinctions in biophysical properties in the N-termini between MECP2-E1 and E2 lead to variable protein stabilities and DNA binding dynamics. This review describes the steps taken from the discovery of MECP2, the description of its key functions and its association with RTT, to the emergence of evidence revealing how MECP2 isoforms are differentially regulated at the transcriptional, post-transcriptional and post-translational levels.

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“…Kir4.1 is an inwardly rectifying potassium channel that is responsible for a majority of the astrocytic potassium buffering [81]. Astrocytes from MeCP2-deficient mice express low level of Kir4.1 and subsequent elevated levels of extracellular potassium concentration [82], suggesting a role for astrocytic MeCP2 in the regulation of neuronal excitability [82]. Due to their peri-synaptic location, astrocytes could drive the elevated release of glutamate detected in RTT [31,79] modulating functional gamma oscillations known to underlie cognitive behavior [83].…”

Section: Introductionmentioning

confidence: 99%

Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic

Kadam

Sullivan

Goyal

et al. 2019

IJMS

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Rett syndrome (RTT) and CDKL5 deficiency disorder (CDD) are two rare X-linked developmental brain disorders with overlapping but distinct phenotypic features. This review examines the impact of loss of methyl-CpG-binding protein 2 (MeCP2) and cyclin-dependent kinase-like 5 (CDKL5) on clinical phenotype, deficits in synaptic- and circuit-homeostatic mechanisms, seizures, and sleep. In particular, we compare the overlapping and contrasting features between RTT and CDD in clinic and in preclinical studies. Finally, we discuss lessons learned from recent clinical trials while reviewing the findings from pre-clinical studies.

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Glial Dysfunction in MeCP2 Deficiency Models: Implications for Rett Syndrome

Cited by 34 publications

References 145 publications

Differential brain region‐specific expression of MeCP2 and BDNF in Rett Syndrome patients: a distinct grey‐white matter variation

Differential brain region‐specific expression of MeCP2 and BDNF in Rett Syndrome patients: a distinct grey‐white matter variation

Regulation, diversity and function of MECP2 exon and 3′UTR isoforms

Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic

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