Evaluation of Rett Syndrome Symptom Improvement by Metabolic Modulators in <i>Mecp2</i>‐Mutant Mice

Buchovecky, Christie; Hill, Misty G.; Borkey, Jennifer M.; Kyle, Stephanie M.; Justice, Monica J.

doi:10.1002/9780470942390.mo130157

Cited by 5 publications

(5 citation statements)

References 26 publications

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“…29,30 In experimental studies using mice and rats, overnight fasting is commonly performed before measurement of plasma lipid levels. [31][32][33] One study has shown that fasting has significant impacts on several parameters related to lipid metabolism in the rat liver. 34 In our study, we found that the levels of TC, TG, HDL-C and LDL-C in both the chow diet group and the high cholesterol diet group showed no significant changes from baseline during 24 h of fasting and that the fasting values were similar to the corresponding plasma lipid levels in the non-fasted state.…”

Section: Discussionmentioning

confidence: 99%

Fasting is not required for measuring plasma lipid levels in rabbits

Wang

Liu

et al. 2019

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Plasma lipid and glucose levels are important parameters for evaluating the onset and development of metabolic and cardiovascular diseases. In clinical and experimental studies of humans or mice, fasting is often required before testing plasma lipid and glucose levels. The rabbit is a valuable animal model for cardiovascular disease research. However, whether fasting is necessary for measuring plasma lipid and glucose levels in rabbits remains unclear. In the current study, 12 healthy Japanese white rabbits (males weighing 2.5–3.0 kg) were randomly divided into a chow diet group ( n = 6) and a high cholesterol diet group ( n = 6). They were fed either a standard chow diet or a chow diet supplemented with 0.5% cholesterol and 3% corn oil for 12 weeks. After 12 weeks, the plasma levels of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and glucose were measured before and after various fasting durations (8, 12, 16, 20 and 24 h). The results showed that there were no significant differences in lipid levels between the fasting and non-fasting samples, whereas glucose levels were lower after 8 h of fasting than in the absence of fasting. Moreover, the glucose levels were restored to normal after 8 h of refeeding. These results indicate that fasting does not affect plasma lipid values in rabbits but that fasting is important for determining the glucose level in rabbits. These findings may be helpful for future rabbit experiments and beneficial for animal welfare.

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Section: Discussionmentioning

confidence: 99%

Fasting is not required for measuring plasma lipid levels in rabbits

Wang

Liu

et al. 2019

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“…In our previous successful screen using a DMD fish model we used birefringence as the primary outcome (Waugh et al, 2014), though we have successfully used movement (measured using the same methodology as described in the present screen) as an outcome for testing therapies in targeted screening in other models of related myopathies (Gibbs et al, 2013a; Robb et al, 2011; Sabha et al, 2016). The mouse screen was performed using a technical strategy that we advanced for studying a mouse model of Rett Syndrome (Buchovecky et al, 2013a,b). Our screen with the Rett Syndrome mouse used a similar number of breeding pairs, tested offspring number, and a G1 dominant modifier approach, and uncovered several genetic loci that modify the Rett mouse phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…A rapid strategy for applying forward genetics to identify modifiers in mice is to use the super mutagen N-ethyl-N-nitrosourea (ENU) (Geister et al, 2018). We have previously utilized an ENU-based genetic screen to uncover second site gene modifiers in a mouse model of Rett syndrome (Buchovecky et al, 2013a,b). To date, however, ENU mutagenesis modifier testing has yet to be applied to any mouse models of muscle disease.…”

Section: Introductionmentioning

confidence: 99%

Failure to identify modifiers of NEBULIN related nemaline myopathy in two pre-clinical models of the disease

et al. 2019

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Nemaline myopathy is a rare neuromuscular disorder that affects 1 in 50,000 live births, with prevalence as high as 1 in 20,000 in certain populations. 13 genes have been linked to nemaline myopathy (NM), all of which are associated with the thin filament of the muscle sarcomere. Of the 13 associated genes, mutations in NEBULIN (NEB) accounts for up to 50% of all cases. Currently, the disease is incompletely understood and there are no available therapeutics for patients. To address this urgent need for effective treatments for patients affected by NM, we conducted a large scale chemical screen in a zebrafish model of NEB-related NM and an N-ethyl-N-nitrosourea (ENU)-based genetic screen in a mouse model of NEB exon 55 deletion, the most common NEB mutation in NM patients. Neither screen was able to identify a candidate for therapy development, highlighting the need to transition from conventional chemical therapeutics to gene-based therapies for the treatment of NM.

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“…For example, we could sample biomarkers in patient tissues, such as muscle, or fluids more accessible than the brain. Take for example genes involved in lipid and cholesterol metabolism, whose expression is controlled by MECP2 in brain cortex and liver (Buchovecky et al, 2013a; Kyle et al, 2016). The concept that organ-specific diseases express molecular phenotypes in multiple tissues other than the affected organ has been tested comprehensively in mouse models of organ-specific pathologies (Kozawa et al, 2018).…”

Section: Why Is Rett Syndrome An Ideal Neurodevelopmental Disorder Tomentioning

confidence: 99%

Molecular Systems Biology of Neurodevelopmental Disorders, Rett Syndrome as an Archetype

Faúndez

Wynne

Crocker

et al. 2019

Front. Integr. Neurosci.

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Neurodevelopmental disorders represent a challenging biological and medical problem due to their genetic and phenotypic complexity. In many cases, we lack the comprehensive understanding of disease mechanisms necessary for targeted therapeutic development. One key component that could improve both mechanistic understanding and clinical trial design is reliable molecular biomarkers. Presently, no objective biological markers exist to evaluate most neurodevelopmental disorders. Here, we discuss how systems biology and “omic” approaches can address the mechanistic and biomarker limitations in these afflictions. We present heuristic principles for testing the potential of systems biology to identify mechanisms and biomarkers of disease in the example of Rett syndrome, a neurodevelopmental disorder caused by a well-defined monogenic defect in methyl-CpG-binding protein 2 (MECP2). We propose that such an approach can not only aid in monitoring clinical disease severity but also provide a measure of target engagement in clinical trials. By deepening our understanding of the “big picture” of systems biology, this approach could even help generate hypotheses for drug development programs, hopefully resulting in new treatments for these devastating conditions.

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Evaluation of Rett Syndrome Symptom Improvement by Metabolic Modulators in Mecp2‐Mutant Mice

Cited by 5 publications

References 26 publications

Fasting is not required for measuring plasma lipid levels in rabbits

Fasting is not required for measuring plasma lipid levels in rabbits

Failure to identify modifiers of NEBULIN related nemaline myopathy in two pre-clinical models of the disease

Molecular Systems Biology of Neurodevelopmental Disorders, Rett Syndrome as an Archetype

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