Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice
Open accessAbstract
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 that Mecp2 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 when Mecp2 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.
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Elevated peripheral lipids may be a biomarker for RTT patients who may respond to statin drugs.
“Interestingly, lovastatin does not have a strong therapeutic effect on B6.Mecp2tm1.1Bird male mice, supporting the idea that elevated peripheral lipids may be a biomarker for those patients who may respond to statin drugs [188].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [188]
The Discussion argues against using elevated serum cholesterol to identify statin responders: it reports improved motor deficits with fluvastatin in female mice whose serum cholesterol was unchanged. It instead proposes investigating plasma 24S-hydroxycholesterol as a possible biomarker of brain cholesterol metabolism that might help identify patients for treatment; that is not a claim that elevated peripheral lipids predict response. (LLM, conf=0.86)
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Experimental — accuracy not yet measuredPharmacological strategies aimed at lowering total cholesterol levels, including statins, might not adequately address the underlying defect and could even prove ineffective or detrimental in RTT.
“Accordingly, pharmacological strategies aimed at lowering total cholesterol levels, including statins, might not adequately address the underlying defect and could even prove ineffective or detrimental, as supported by results obtained from both preclinical studies and a phase II clinical trial in RTT patients (Villani et al., 2016).”
From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Villani et al., 2016
The Discussion reports that lovastatin did not improve motor performance or survival in the B6 Mecp2-null mice studied, and suggests its effects may not result from direct inhibition of cholesterol synthesis. This supports caution about cholesterol-lowering strategies, but the paper does not establish that they are detrimental or report results from a phase II trial in RTT patients. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA second study performed on Mecp2-deficient mice with a different genetic background showed no effect of lovastatin.
“whereas a second study performed on Mecp2-deficient mice with a different genetic background show no effect of lovastatin [81].”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [81]
Lovastatin does not have a strong therapeutic effect on B6.Mecp2tm1.1Bird male mice.
“Interestingly, lovastatin does not have a strong therapeutic effect on B6.Mecp2tm1.1Bird male mice, supporting the idea that elevated peripheral lipids may be a biomarker for those patients who may respond to statin drugs [188].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [188]
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“…2005; J.-P. Liu et al., 2010; Pfrieger, 2003), as well as by accumulating evidence of altered brain cholesterol metabolism in RTT (Ben-Shachar et al., 2009; Buchovecky et al., 2013b; Lopez et al., 2017; Lütjohann et al., 2018; Urdinguio et al., 2008; Villani et al., 2016; Zandl-Lang et al., 2022).”
Lung Defects Contribute to Respiratory Symptoms in a Mecp2-mutant Mouse Model of Rett Syndrome
Vashi, N. (2021) · TSpace (University of Toronto)
Tapía, P., Rivera, B. I., Espinoza, C. S., Stolzenbach, F., Yañez, M. J., & Kerr, B. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27052348
- Authors
- Villani, C., Sacchetti, G., Bagnati, R., Passoni, A., Fusco, F., Carli, M., & Invernizzi, R. W.
- Affiliations
- Mario Negri Institute for Pharmacological Research (IT)
- Corresponding author
- Invernizzi, Roberto William
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-11-28
- Volume
- 5
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5132339
- OpenAlex
- W2559625605
- Cited by
- 20
- References
- 41
- Citations by year
- 2026: 2 · 2024: 4 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 1
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-06-29)
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Istituto di Ricerche Farmacologiche Mario Negri (Intramural funding)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- lovastatin, Rett syndrome, Mecp2-null mice, statins, brain cholesterol homeostasis, 24S-hydroxycholesterol, motor impairment, survival, biomarkers, cholesterol metabolism
- MeSH terms
- Animals, Disease Models, Animal, Lovastatin, Mice, Inbred C57BL, Motion, Rett Syndrome, Survival Analysis, Treatment Outcome, Mice, Knockout, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Methyl-CpG-Binding Protein 2
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