Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice
Previous studies provided evidence for the alteration of brain cholesterol homeostasis in 129.Mecp2-null mice, an experimental model of Rett syndrome. The efficacy of statins in improving motor symptoms and prolonging survival of mutant mice suggested a potential role of statins in the therapy of Rett syndrome. In the present study, we show thatMecp2 deletion had no effect on brain and reduced serum cholesterol levels and lovastatin (1.5 mg/kg, twice weekly as in the previous study) had no effects on motor deficits and survival whenMecp2 deletion was expressed on a background strain (C57BL/6J; B6) differing from that used in the earlier study. These findings indicate that the effects of statins may be background specific and raise important issues to consider when contemplating clinical trials. The reduction of the brain cholesterol metabolite 24S-hydroxycholesterol (24S-OHC) found in B6.Mecp2-null mice suggests the occurrence of changes in brain cholesterol metabolism and the potential utility of using plasma levels of 24S-OHC as a biomarker of brain cholesterol homeostasis in RTT.DOI:http://dx.doi.org/10.7554/eLife.22409.001
Rett syndrome (RTT; OMIM 312750), a progressive neurological disorder, is caused by mutations in methyl-CpG-binding protein 2 (MECP2; OMIM 300005), a ubiquitously expressed factor. A genetic suppressor screen designed to identify therapeutic targets surprisingly revealed that downregulation of the cholesterol biosynthesis pathway improves neurological phenotypes in Mecp2 mutant mice. Here, we show that MeCP2 plays a direct role in regulating lipid metabolism. Mecp2 deletion in mice results in a host of severe metabolic defects caused by lipid accumulation, including insulin resistance, fatty liver, perturbed energy utiliza...
Condition: Rett SyndromeIntervention: Drug: LovastatinSponsors: Montefiore Medical Center; Rett Syndrome Research TrustRecruiting - verified September 2015