Non–cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology

Ballas, Nurit; Lioy, Daniel T.; Mandel, Gail

doi:10.1038/nn.2275

Cited by 423 publications

(486 citation statements)

References 52 publications

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“…In addition, the expression of transgenic MeCP2 in glial cells in the transgenic mice described in this report could contribute to the behavioral amelioration and might explain the different results observed. 23,28 Do our results mean that MeCP2-e1 and MeCP2-e2 are practically interchangeable? Life span, body weight control and anxiety were equally rescued by both isoforms, suggesting equal function at similar levels of expression.…”

Section: Discussionmentioning

confidence: 92%

“…Co-staining of transgenic MeCP2 and the intermediate filament marker glial fibrillary acidic protein (GFAP) indicated that none of the transgenic lines express MeCP2 in astrocytes at detectable levels (Supplementary Figure 2a). However, as it has been shown that endogenous MeCP2 expression in glial cells is not easily revealed due to its low levels, 23 we analyzed the expression of the transgenes in primary cultures of mixed cortical cells and found expression of MeCP2 transgenes in some GFAP-positive glial cells in the three transgenic lines studied (Supplementary Figure 2b).…”

Section: Expression Of Isoform-specific Cdnas In Transgenic Micementioning

confidence: 99%

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Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes

Kerr

Sáez

et al. 2011

Eur J Hum Genet

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Rett syndrome (RTT) is a disorder that affects patients' ability to communicate, move and behave. RTT patients are characterized by impaired language, stereotypic behaviors, frequent seizures, ataxia and sleep disturbances, with the onset of symptoms occurring after a period of seemingly normal development. RTT is caused by mutations in methyl-CpG binding protein 2 (MECP2), an X-chromosome gene encoding for MeCP2, a protein that regulates gene expression. MECP2 generates two alternative splice variants encoding two protein isoforms that differ only in the N-terminus. Although no functional differences have been identified for these splice variants, it has been suggested that the RTT phenotype may occur in the presence of a functional MeCP2-e2 protein. This suggests that the two isoforms might be functionally distinct. Supporting this notion, the two variants show regional and age-related differences in transcript abundance. Here, we show that transgenic expression of either the MeCP2-e1 or MeCP2-e2 splice variant results in prevention of development of RTT-like phenotypic manifestations in a mouse model lacking Mecp2. Our results indicate that the two MeCP2 splice variants can substitute for each other and fulfill the basic functions of MeCP2 in the mouse brain.

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Section: Discussionmentioning

confidence: 92%

Section: Expression Of Isoform-specific Cdnas In Transgenic Micementioning

confidence: 99%

Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes

Kerr

Sáez

et al. 2011

Eur J Hum Genet

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“…A clue stems from the realization that glia and astrocytes contribute to the pathology of both ALS and Rett syndrome (Lioy et al 2011;Phatnani et al 2013;Yasui et al 2013). A common trait shared between ALS and Rett syndrome is a non-cell-autonomous-mediated neuronal death, and glial cells expressing either ALS mutant proteins or reduced levels of MeCP2 secrete a neurotoxin that leads to inhibition of dendritic complexity and neuron death (Ballas et al 2009). Additionally, recent studies have shown that dysregulation of MeCP2 protein, similar to FUS, preferentially affects expression of long genes (Sugino et al 2014;Gabel et al 2015).…”

Section: Discussionmentioning

confidence: 99%

ALS mutations in TLS/FUS disrupt target gene expression

Coady

Manley

2015

Genes Dev.

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Amyotrophic lateral sclerosis (ALS) is caused by mutations in a number of genes, including the gene encoding the RNA/DNA-binding protein translocated in liposarcoma or fused in sarcoma (TLS/FUS or FUS). Previously, we identified a number of FUS target genes, among them MECP2. To investigate how ALS mutations in FUS might impact target gene expression, we examined the effects of several FUS derivatives harboring ALS mutations, such as R521C (FUS C ), on MECP2 expression in transfected human U87 cells. Strikingly, FUS C and other mutants not only altered MECP2 alternative splicing but also markedly increased mRNA abundance, which we show resulted from sharply elevated stability. Paradoxically, however, MeCP2 protein levels were significantly reduced in cells expressing ALS mutant derivatives. Providing a parsimonious explanation for these results, biochemical fractionation and in vivo localization studies revealed that MECP2 mRNA colocalized with cytoplasmic FUS C in insoluble aggregates, which are characteristic of ALS mutant proteins. Together, our results establish that ALS mutations in FUS can strongly impact target gene expression, reflecting a dominant effect of FUS-containing aggregates.

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“…Glial-derived lipoproteins containing cholesterol stimulate axon growth 27 and transcription of genes involved in dendrite and synapse development 28 in primary rat retinal ganglion cells; their co-culture with glial cells enhances synaptic activity and neurite outgrowth and branching in Purkinje neurons, 29 and cholesterol deficiency inhibits dendrite outgrowth in primary cortical and hippocampal neurons. 30 Impairments in astrocytic function are increasingly recognized as a culprit in neuronal dysfunction in neurodegenerative diseases, 31 such as amyotrophic lateral sclerosis, 32 Rett's syndrome, 33,34 lysosomal disorders, 35 Alzheimer's disease, 36 and HD. 16 Accordingly, astrocyte kir4.1 ion channel deficits contribute to neuronal dysfunction in Figure 4b is the same.…”

Section: Discussionmentioning

confidence: 99%

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

et al. 2014

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In the adult brain, neurons require local cholesterol production, which is supplied by astrocytes through apoE-containing lipoproteins. In Huntington's disease (HD), such cholesterol biosynthesis in the brain is severely reduced. Here we show that this defect, occurring in astrocytes, is detrimental for HD neurons. Astrocytes bearing the huntingtin protein containing increasing CAG repeats secreted less apoE-lipoprotein-bound cholesterol in the medium. Conditioned media from HD astrocytes and lipoprotein-depleted conditioned media from wild-type (wt) astrocytes were equally detrimental in a neurite outgrowth assay and did not support synaptic activity in HD neurons, compared with conditions of cholesterol supplementation or conditioned media from wt astrocytes. Molecular perturbation of cholesterol biosynthesis and efflux in astrocytes caused similarly altered astrocyteneuron cross talk, whereas enhancement of glial SREBP2 and ABCA1 function reversed the aspects of neuronal dysfunction in HD. These findings indicate that astrocyte-mediated cholesterol homeostasis could be a potential therapeutic target to ameliorate neuronal dysfunction in HD. Huntington's disease (HD) is an adult-onset neurodegenerative disorder characterized by cell loss mainly in the striatum and cortex. Its pathophysiology is linked to an expanded CAG repeat in the IT-15 gene, which leads to an elongated polyQ tract in huntingtin (HTT) protein. No disease-modifying treatment is available for HD and novel pathophysiological insights and therapeutic strategies are needed. 1 Lipids are vital to brain health and function. Accordingly, the brain has a local source of cholesterol, 2 and a breakdown of cholesterol synthesis causes brain malformations and impaired cognitive function. 3,4 Cholesterol metabolism is disrupted in HD 5,6 as revealed by transcriptional, biochemical, and mass spectrometry analyses in HD rodent models. 7,8 This dysregulation is linked to a specific action of mutant HTT on sterol-regulatory-element-binding proteins (SREBPs) and on its target genes, whose reduced transcription leads to lower brain cholesterol levels. 7 In HD humans, brain cholesterol homeostasis is affected since pre-symptomatic stages, as determined by measurement of the brain-specific cholesterol catabolite 24-S-hydroxy-cholesterol (24OHC). 9,10 However, it remains unclear how reduced brain cholesterol would become pathological for HD neurons.In adulthood, astrocytes produce cholesterol, which is secreted as a complex with apolipoprotein (apo) E lipoproteins and delivered to neurons. 11,12 Mutant HTT is expressed in glial cells, 13,14 and transgenic mice overexpressing mutant HTT in astrocytes show age-dependent neurological symptoms. 15,16 Additionally, primary astrocytes overexpressing full-length human mutant HTT show reduced mRNA levels of cholesterol biosynthetic genes, along with impaired cellular production and secretion of apoE. 8 Here we employed molecular and cellular tools to test the impact of cholesterol perturbation between astrocytes and neur...

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Non–cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology

Cited by 423 publications

References 52 publications

Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes

Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes

ALS mutations in TLS/FUS disrupt target gene expression

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

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