A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome
Monica Justice and colleagues performed a genetic suppressor screen in Mecp2-null mice, which recapitulate symptoms of Rett syndrome, a neurological disease with autistic features. They identify a nonsense suppressor mutation in Sqle, which encodes a rate-limiting enzyme in cholesterol synthesis, and show that treatment of Mecp2 mutant mice with statins improves symptoms and increases longevity.
Mutations in MECP2, encoding methyl CpG-binding protein 2, cause Rett syndrome, the most severe autism spectrum disorder.
Re-expressing Mecp2 in symptomatic Mecp2-null mice markedly improves function and longevity, providing hope that therapeutic intervention is possible in humans.
To identify pathways in disease pathology for therapeutic intervention, we carried out a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis suppressor screen in Mecp2-null mice and isolated five suppressors that ameliorate the symptoms of Mecp2 loss.
We show that a stop codon mutation in Sqle, encoding squalene epoxidase, a rate-limiting enzyme in cholesterol biosynthesis, underlies suppression in one line.
Subsequently, we also show that lipid metabolism is perturbed in the brains and livers of Mecp2-null male mice.
Consistently, statin drugs improve systemic perturbations of lipid metabolism, alleviate motor symptoms and confer increased longevity in Mecp2 mutant mice.
Our genetic screen therefore points to cholesterol homeostasis as a potential target for the treatment of patients with Rett syndrome.
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