Metabolomic Fingerprint of Mecp2-Deficient Mouse Cortex: Evidence for a Pronounced Multi-Facetted Metabolic Component in Rett Syndrome

Abstract

Using unsupervised metabolomics, we defined the complex metabolic conditions in the cortex of a mouse model of Rett syndrome (RTT). RTT, which represents a cause of mental and cognitive disabilities in females, results in profound cognitive impairment with autistic features, motor disabilities, seizures, gastrointestinal problems, and cardiorespiratory irregularities. Typical RTT originates from mutations in the X-chromosomal methyl-CpG-binding-protein-2 (Mecp2) gene, which encodes a transcriptional modulator. It then causes a deregulation of several target genes and metabolic alterations in the nervous system and peripheral organs. We identified 101 significantly deregulated metabolites in the Mecp2-deficient cortex of adult male mice; 68 were increased and 33 were decreased compared to wildtypes. Pathway analysis identified 31 mostly upregulated metabolic pathways, in particular carbohydrate and amino acid metabolism, key metabolic mitochondrial/extramitochondrial pathways, and lipid metabolism. In contrast, neurotransmitter-signaling is dampened. This metabolic fingerprint of the Mecp2-deficient cortex of severely symptomatic mice provides further mechanistic insights into the complex RTT pathogenesis. The deregulated pathways that were identified—in particular the markedly affected amino acid and carbohydrate metabolism—confirm a complex and multifaceted metabolic component in RTT, which in turn signifies putative therapeutic targets. Furthermore, the deregulated key metabolites provide a choice of potential biomarkers for a more detailed rating of disease severity and disease progression.

Oral Feeding of an Antioxidant Cocktail as a Therapeutic Strategy in a Mouse Model of Rett Syndrome: Merits and Limitations of Long-Term Treatment

“…This treatment successfully improved the general phenotypic appearance of Mecp2 −/ y mice, as it stimulated their gain of weight, their growth, and their BMI. Hence, a beneficial impact on the distorted metabolic conditions in RTT [ 60 , 61 ] can be assumed. This indicates that the administered AOs did not only affect the central nervous system but also modulated the functions of peripheral organs.…”

“…Blood glucose levels were significantly reduced in Mecp2 −/ y mice, which may have been due to the intensified carbohydrate metabolism detected in our recent metabolomics study on Mecp2 −/ y cortex [ 61 ]. An amelioration of blood glucose contents in Mecp2 −/ y mice was observed upon AO treatment.…”

MeCP2 Is an Epigenetic Factor That Links DNA Methylation with Brain Metabolism

“…The metabolic fingerprinting results had detected elevated AMP and ADP levels. This may lead to an observed increase in AMPK-mediated activation of glycolysis and TCA [ 181 , 212 ]. Hence, it is believed that impaired function of MeCP2 can disturb the AMPK signaling pathway and that it results in several symptoms in RTT patients, including high blood glucose and insulin resistance.…”

“…The study showcased that 101 metabolites that are involved in multiple metabolic pathways, including energy metabolism, lipid metabolism, amino acid metabolism, nucleotide metabolism and micronutrient metabolism, were significantly dysregulated. The researchers suggested that these dysregulated metabolites could become potential biomarkers for RTT, as clinical symptoms progressed [ 212 ]. Another study also indicated the abnormal transcript levels of HMG-CoA reductase, squalene epoxidase, and lanosterol synthase in the liver of Mecp2 null male mice at the age of 8 weeks.…”

Nuclear and Cytoplasmatic Players in Mitochondria-Related CNS Disorders: Chromatin Modifications and Subcellular Trafficking

“…Alterations in amino acid and carbohydrate metabolism have recently been confirmed in the cortex of severely symptomatic male MeCP2 KO mice [52]. Nonetheless, in the case of MeCP2-targeted gene expression profiling carried out since early development [53,54] and/or in different tissues [55] might be fundamental in distinguishing between geneticdriven primary defects and secondary features provoked by the accumulation of damages.…”