A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome

Abstract

SummaryMutations in methyl CpG binding protein 2 (MECP2) cause Rett Syndrome, the most severe autism spectrum disorder. Re-expressing Mecp2 in symptomatic Mecp2 null mice dramatically improves function and longevity, providing hope that therapeutic intervention is possible in humans. To identify pathways in disease pathology for therapeutic intervention, a dominant ENU mutagenesis suppressor screen was carried out in Mecp2 null mice. Five suppressors that ameliorate symptoms of Mecp2 loss were isolated. Here we show that a stop codon mutation in squalene epoxidase (Sqle), a rate-limiting enzyme in cholesterol biosynthesis underlies suppression in one line. Subsequently, we show that lipid metabolism is perturbed in the brain and liver of Mecp2 null males. Consistently, statin drugs improve systemic perturbations of lipid metabolism, alleviate motor symptoms and confer increased longevity in Mecp2 mutant mice. The genetic screen therefore points to cholesterol homeostasis as a potential target for the treatment of Rett patients.

Loss of MeCP2 in cholinergic neurons causes part of RTT-like phenotypes via α7 receptor in hippocampus

“…Mutations in specific nicotinic receptors can even cause a genetically transmissible form of epilepsy [27]. Moreover, decreases in cholinergic markers have been correlated with clinical severity in RTT patients [28,29]. The link between cholinergic systems and specific RTT phenotypes led us to hypothesize that dysfunction in cholinergic neurons might be involved in RTT.…”

PTP1B inhibition suggests a therapeutic strategy for Rett syndrome

“…In an alternative approach involving mutagenesis screens in Mecp2-mutant mice, mutations in squalene epoxidase, the rate-limiting enzyme in cholesterol biosynthesis, were identified as suppressing RTT-associated phenotypes. Interestingly, cholesterol metabolism is altered and cholesterol levels are elevated in the brains of Mecp2 -/y male mice, all of which prompted the testing of statins with positive effects on some, but not all, categories of symptoms (14). Loss of function of MECP2 has also been associated with disruption of signaling through the AKT/mTOR pathway (15).…”

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

“…One of the mitigating mutations introduced a premature stop codon in Sqle (squalene epoxidase), which encodes a key cholesterol biosynthesis enzyme. The authors showed that treatment of Mecp2 À/À mice with cholesterol-lowering statin drugs significantly improved motor function and lifespan, 73 suggesting that this widely used class of drugs may benefit individuals with Rett syndrome. A recently completed phase 2 clinical trial (NCT02563860) is evaluating this hypothesis, with results forthcoming (see Clinical Trials in Web Resources).…”

“…A similar ENU-based mutagenesis screen identified modifier genes in the Mecp2 À/À (methyl CpG binding protein 2) mouse model of Rett syndrome (MIM: 312750). 73 As in humans,…”