A role for metabolism in Rett syndrome pathogenesis

Justice, Monica J.; Buchovecky, Christie; Kyle, Stephanie M.; Djukic, Aleksandra

doi:10.4161/rdis.27265

Cited by 49 publications

(45 citation statements)

References 28 publications

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“…Four mutations (Aacs, Apoa5, Atp8a1, Tm7sf2) support previous publications that lipid metabolism is a primary pathway for pathogenesis Justice et al 2013;Segatto et al 2014;Kyle et al 2016). The founding lesion in this pathway occurred in Sqle, a rate-limiting enzyme in cholesterol synthesis.…”

Section: Lipid Homeostasissupporting

confidence: 84%

Suppressor mutations in Mecp2-null mice implicate the DNA damage response in Rett syndrome pathology

et al. 2020

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Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT). To identify functional pathways that could inform therapeutic entry points, we carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU). Here, we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3177 Mecp2/Y genomes. Whole-exome sequencing, genetic crosses, and association analysis identified 22 candidate genes. Additional lesions in these candidate genes or pathway components associate variant alleles with phenotypic improvement in 30 lines. A network analysis shows that 63% of the genes cluster into the functional categories of transcriptional repression, chromatin modification, or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that modulate synaptic signaling or lipid homeostasis. Mutations in genes that function in the DNA damage response (DDR) also improve phenotypes in Mecp2/Y mice. Association analysis was successful in resolving combinatorial effects of multiple loci. One line, which carries a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8, endonuclease (Rbbp8, also known as CtIP), which regulates a DDR choice in double-stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests that the balance between homology-directed repair and nonhomologous end joining is important for neuronal cells. In this and other lines, two suppressor mutations confer greater improvement than one alone, suggesting that combination therapies could be effective in RTT.

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Section: Lipid Homeostasissupporting

confidence: 84%

Suppressor mutations in Mecp2-null mice implicate the DNA damage response in Rett syndrome pathology

et al. 2020

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“…Affected subjects, almost exclusively females, show progressive loss of acquired motor and cognitive skills and develop additional symptoms including stereotypic hand movements, drug-resistant seizures, breathing and autonomic dysfunctions (Chahrour and Zoghbi, 2007). Increased cholesterol plasma levels and changes in the activity/expression of genes and proteins involved in the cellular uptake, synthesis and feedback regulation of circulating cholesterol have recently been found in RTT individuals carrying MECP2 mutations (Grillo et al, 2013; Justice et al, 2013; Segatto et al, 2014), However, only one-third of RTT patients show elevated levels of plasma cholesterol (Justice et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice

Villani

Sacchetti

Bagnati

et al. 2016

eLife

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Previous studies provided evidence for the alteration of brain cholesterol homeostasis in 129.Mecp2-null mice, an experimental model of Rett syndrome. The efficacy of statins in improving motor symptoms and prolonging survival of mutant mice suggested a potential role of statins in the therapy of Rett syndrome. In the present study, we show that Mecp2 deletion had no effect on brain and reduced serum cholesterol levels and lovastatin (1.5 mg/kg, twice weekly as in the previous study) had no effects on motor deficits and survival when Mecp2 deletion was expressed on a background strain (C57BL/6J; B6) differing from that used in the earlier study. These findings indicate that the effects of statins may be background specific and raise important issues to consider when contemplating clinical trials. The reduction of the brain cholesterol metabolite 24S-hydroxycholesterol (24S-OHC) found in B6.Mecp2-null mice suggests the occurrence of changes in brain cholesterol metabolism and the potential utility of using plasma levels of 24S-OHC as a biomarker of brain cholesterol homeostasis in RTT.DOI: http://dx.doi.org/10.7554/eLife.22409.001

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“…Colon and crypt shortening has been observed in animal models of colitis and inflammatory bowel disease, as well as in mice when dyslipidemia was induced with a high-fat diet [23–26]. Dyslipidemia has been observed in the Mecp2 −/− animals and in a significant number of Rett patients [27]. Interestingly, Mecp2 − /− animals subjected to pharmacotherapy to improve lipid metabolism showed amelioration of motor symptoms and decreased lethality [28], but the possibility that the pharmacological restoration of lipid homeostasis is capable to ameliorate the intestinal phenotype in the Mecp2 −/− animals has not been explored.…”

Section: Discussionmentioning

confidence: 99%

“…Other explanation might be that cells in the surface can be affected by alterations in the intestinal contents delivered from the small intestine into the colon. For example, bile acids are known to induce colitis in mice and humans [34, 35], and even when there is no available data for fecal bile acid contents in RTT patients or animal models, scattered reports of RTT patients hospitalized due to liver failure and many others subjected to gallbladder removal are available [27]. More recently, it has been published that Rett patients presented with a less diverse microbiota than healthy subjects [36], which could affect gastrointestinal function, but this possibility has not been explored in the mouse model yet.…”

Section: Discussionmentioning

confidence: 99%

Severe changes in colon epithelium in the Mecp2-null mouse model of Rett syndrome

et al. 2016

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BackgroundRett syndrome is best known due to its severe and devastating symptoms in the central nervous system. It is produced by mutations affecting the Mecp2 gene that codes for a transcription factor. Nevertheless, evidence for MECP2 activity has been reported for tissues other than those of the central nervous system. Patients affected by Rett presented with intestinal affections whose origin is still not known. We have observed that the Mecp2-null mice presented with episodes of diarrhea, and decided to study the intestinal phenotype in these mice.Methods Mecp2-null mice or bearing the conditional intestinal deletion of MECP2 were used. Morphometirc and histologic analysis of intestine, and RT-PCR, western blot and immunodetection were perfomed on intestinal samples of the animals. Electrical parameters of the intestine were determined by Ussing chamber experiments in freshly isolated colon samples.ResultsFirst we determined that MECP2 protein is mainly expressed in cells of the lower part of the colonic crypts and not in the small intestine. The colon of the Mecp2-null mice was shorter than that of the wild-type. Histological analysis showed that epithelial cells of the surface have abnormal localization of key membrane proteins like ClC-2 and NHE-3 that participate in the electroneutral NaCl absorption; nevertheless, electrogenic secretion and absorption remain unaltered. We also detected an increase in a proliferation marker in the crypts of the colon samples of the Mecp2-null mice, but the specific silencing of Mecp2 from intestinal epithelium was not able to recapitulate the intestinal phenotype of the Mecp2-null mice.ConclusionsIn summary, we showed that the colon is severely affected by Mecp2 silencing in mice. Changes in colon length and epithelial histology are similar to those observed in colitis. Changes in the localization of proteins that participate in fluid absorption can explain watery stools, but the exclusive deletion of Mecp2 from the intestine did not reproduce colon changes observed in the Mecp2-null mice, indicating the participation of other cells in this phenotype and the complex interaction between different cell types in this disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s40348-016-0065-3) contains supplementary material, which is available to authorized users.

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A role for metabolism in Rett syndrome pathogenesis

Cited by 49 publications

References 28 publications

Suppressor mutations in Mecp2-null mice implicate the DNA damage response in Rett syndrome pathology

Suppressor mutations in Mecp2-null mice implicate the DNA damage response in Rett syndrome pathology

Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice

Severe changes in colon epithelium in the Mecp2-null mouse model of Rett syndrome

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