Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis

Abstract

Mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) are the principal cause of Rett syndrome, a progressive neurodevelopmental disorder afflicting 1 in 10,000 to 15,000 females. Studies using hemizygous Mecp2 mouse models have revealed disruptions to some aspects of their lipid metabolism including a partial suppression of cholesterol synthesis in the brains of mature Mecp2 mutants. The present studies investigated whether this suppression is evident from early neonatal life, or becomes manifest at a later stage of development. We measured the rate of cholesterol synthesis, in vivo, in the brains of male Mecp2−/y and their Mecp2+/y littermates at 7, 14, 21, 28, 42 and 56 days of age. Brain weight was consistently lower in the Mecp2−/y mice than in their Mecp2+/y controls except at 7 days of age. In the 7- and 14-day-old mice there was no genotypic difference in the rate of brain cholesterol synthesis but, from 21 days and later, it was always marginally lower in the Mecp2−/y mice than in age-matched Mecp2+/y littermates. At no age was a genotypic difference detected in either the rate of fatty acid synthesis or cholesterol concentration in the brain. Cholesterol synthesis rates in the liver and lungs of 56-day-old Mecp2−/y mice were normal. The onset of lower rates of brain cholesterol synthesis at about the time closure of the blood brain barrier purportedly occurs might signify a disruption to mechanism(s) that dictate intracellular levels of cholesterol metabolites including oxysterols known to exert a regulatory influence on the cholesterol biosynthetic pathway.

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

“…This fully agrees with recent data showing that Cyp46a1 expression was not affected in B6. Mecp2 -null mice aged 14, 43 or 56 days (Lopez et al, 2017), but is in sharp contrast with previous findings (Buchovecky et al, 2013). However, we found a moderate, but highly significant reduction of brain 24S-OHC in males and confirmed this effect in females Mecp2 +/- mice.…”

“…However, other phenotypes, such as motor deficits, are reproduced in different mouse models of RTT regardless of the genetic background (Lombardi et al, 2015; Samaco et al, 2013). In agreement with our findings, brain cholesterol and the expression of Cyp46a1 was not affected in Mecp2 tm1.1Bird/y mice on the B6 background, aged 7 to 56 days and no changes of brain levels of the cholesterol precursor desmosterol were observed at 7 and 14 days (Lopez et al, 2017). In addition, no increase in serum and brain cholesterol was detected in another line of Mecp2 -null mice, the Mecp2 tm1.1Jae on a B6 background (Buchovecky et al, 2013).…”

MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome

“…Recent identification of mutations that enhance survival of Mecp2 -/y males has established the link between Mecp2 and lipid metabolism (30)(31)(32). Consistent with these findings our results show that Mecp2e1 -/+ females at 12 to 14 weeks of age and Mecp2e1 -/y males at 7 to 11 weeks of age display significant elevation in body fat percent and fat mass without significant elevation in weight on a C57BL6/J background.…”

“…Lipid metabolism was identified in an unbiased screen for rescue of RTT mouse phenotypes (30) and was later shown to result in metabolic alterations in RTT mice (31). Metabolic or oxidative stress alterations have been modified in several therapeutic trials of RTT mouse models (20), with some discrepancies by strain and age (32,33). Since the most promising therapeutics for RTT target metabolic pathways (34), such as AKT/mTOR (35,36), oxidative stress (28,37), and lipid metabolism (30,38), it is imperative to characterize developmental, metabolic, and motor phenotypes in female RTT mouse models.…”

Identification of Correlative Shifts in Indices of Brain Cholesterol Metabolism in the C57BL6/Mecp2tm1.1Bird Mouse, a Model for Rett Syndrome

“…A landmark publication in 2013 reporting that statin treatment had several beneficial effects in a mouse model for Rett syndrome (RS), a neurodevelopmental disorder (Buchovecky et al, ), raised the question of what effects, if any, methyl‐Cpg‐binding protein (MECP2) dysfunction has on cholesterol metabolism in the CNS. This was partially answered by a detailed study of brain cholesterol synthesis rates and concentration in Mecp2 −/y mice at different stages of development (Lopez, Chuang, Posey, & Turley, ). These experiments, carried out in vivo , showed that up until near weaning, the mutant mice had normal rates of brain cholesterol synthesis but after that they were consistently about 15–20% lower than in their age‐matched Mecp +/y controls.…”