Cholesterol Metabolism Is Altered in Rett Syndrome: A Study on Plasma and Primary Cultured Fibroblasts Derived from Patients
Open accessAbstract
Rett (RTT) syndrome is a severe neurological disorder that affects almost exclusively females. Several detectable mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2) are responsible for the onset of the disease. MeCP2 is a key transcription regulator involved in gene silencing via methylation-dependent remodeling of chromatin. Recent data highlight that lipid metabolism is perturbed in brains and livers of MECP2-null male mice. In addition, altered plasma lipid profile in RTT patients has been observed. Thus, the aim of the work is to investigate the protein network involved in cholesterol homeostasis maintenance on freshly isolated fibroblasts and plasma from both RTT and healthy donors. To this end, protein expression of 3-hydroxy-3methyl glutaryl Coenzyme A reductase (HMGR), sterol regulatory element binding proteins (SREBPs), low density lipoprotein receptor (LDLr) and scavenger receptor B-1 (SRB-1) was assessed in cultured skin fibroblasts from unaffected individuals and RTT patients. In addition, lipid profile and the abundance of proprotein convertase subtilisin/kexin type 9 (PCSK9) were analyzed on plasma samples. The obtained results demonstrate that the main proteins belonging to cholesterol regulatory network are altered in RTT female patients, providing the proof of principle that cholesterol metabolism may be taken into account as a new target for the treatment of specific features of RTT pathology.
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General deregulation of the protein network of cholesterol homeostasis, including HMGCR and SREBP1 and 2 expression, has been described in Rett syndrome fibroblasts.
“a general deregulation of the protein network of cholesterol homeostasis, including HMGCR and SREBP1 and 2 expression, was described in RTT fibroblasts (Segatto et al., 2014).”
From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Segatto et al., 2014
The Results and Discussion report an altered cholesterol-homeostasis protein network in RTT fibroblasts, with increased HMGR (HMGCR) and active SREBP-2 protein levels. But the same section explicitly reports no change in active SREBP-1 protein expression, so the claim overstates the finding if it includes SREBP-1 among the deregulated proteins. Page numbers are not provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMetabolic complications are common in RTT.
“Metabolic complications are also common in RTT.”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [16]
The Results and Discussion report significantly higher total and LDL cholesterol in the studied RTT patients than in healthy controls, supporting a specific metabolic alteration. The paper does not establish how common metabolic complications are across people with RTT, or address metabolic complications broadly. (LLM, conf=0.82)
Experimental — accuracy not yet measuredOnly a subset of RTT patients exhibit increased serum cholesterol and/or triglycerides.
“Consistently, only a subset of RTT patients exhibit increased serum cholesterol and/or triglycerides [15,16,173].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [16]
The Results and Discussion report significantly higher total and LDL cholesterol in RTT patients than in healthy controls, supporting the cholesterol portion of the claim. They report no variation in triglycerides and do not establish that the increases occur in only a subset of patients (page unavailable in our copy). (LLM, conf=0.85)
Experimental — accuracy not yet measuredWe reported a dramatic reduction in the activity of HMGCR in RTT fibroblasts.
“Importantly, we reported a dramatic reduction in the activity of HMGCR.”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [75]
A rise in LDLR expression was noted in RTT fibroblasts.
“A rise in LDLR expression was noted in RTT fibroblasts [75].”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [75]
LDLR increase in RTT is also promoted by the decrease in degradative events, as suggested by the fall in PCSK9 plasma levels in RTT individuals.
“Furthermore, LDLR increase is also promoted by the decrease in degradative events, as suggested by the fall in Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9, a protein involved in LDLR degradation) plasma levels in RTT individuals [75].”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [75]
We observed a significant increase of total cholesterol and LDL-cholesterol plasma levels, and a decrease of SR-B1 protein expression in primary fibroblasts derived from RTT patients.
“In agreement with other preclinical and clinical data [77,102], we observed a significant increase of total cholesterol and LDL-cholesterol plasma levels, and a decrease of SR-B1 protein expression in primary fibroblasts derived from RTT patients [75].”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [75]
Our studies support an involvement of cholesterol metabolism in RTT patients harboring mutations in the Mecp2 gene.
“Our studies support an involvement of cholesterol metabolism in RTT patients harboring mutations in Mecp2 gene [14,75].”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [75]
We highlighted a concurrent increase in the protein amount of HMGCR in RTT fibroblasts.
“Together with the reduction in HMGCR activity, we highlighted a concurrent increase in the protein amount of HMGCR in RTT fibroblasts.”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [75]
A similar conclusion that cholesterol metabolism is disrupted was reached in studies with primary cultured fibroblasts from Rett syndrome patients.
“A similar conclusion was reached in studies with primary cultured fibroblasts from Rett syndrome patients (Segatto et al., 2014).”
From 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 (2017) · cites this paper as Segatto et al., 2014
A number of RTT patients present with dyslipidaemia.
“A number of patients present with dyslipidaemia [15,16], elevated plasma leptin and adiponectin [17,18], elevated ammonia [1] and inflammation of the gallbladder, an organ which stores bile for fat digestion [19].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [16]
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A proteomics approach to further highlight the altered inflammatory condition in Rett syndrome
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PTP1B: a new therapeutic target for Rett syndrome
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Aberrant lung lipids cause respiratory impairment in a Mecp2-deficient mouse model of Rett syndrome
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Modulation of Brain Cholesterol Metabolism through CYP46A1 Overexpression for Rett Syndrome
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Behavioral and transcriptomic analyses of mecp 2 function in zebrafish
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Model systems inform rare disease diagnosis, therapeutic discovery and pre-clinical efficacy
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A Review on Rett Syndrome: A Debilitating Neurodevelopmental Disorder
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Rett Syndrome: Thinking Beyond Brain Borders
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Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome
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“Furthermore, a general deregulation of the protein network of cholesterol homeostasis, including HMGCR and SREBP1 and 2 expression, was described in RTT fibroblasts (Segatto et al., 2014).”
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- Authors
- Segatto, M., Trapani, L., Di Tunno, I., Sticozzi, C., Valacchi, G., Hayek, J., & Pallottini, V.
- Affiliations
- Roma Tre University (IT)
- University of Ferrara (IT)
- Azienda Ospedaliera Universitaria Senese (IT)
- Corresponding author
- Pallottini, Valentina
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-08-12
- Volume
- 9
- Issue
- 8
- Pages
- e104834
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4130597
- OpenAlex
- W2068610338
- Cited by
- 80
- References
- 34
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 7 · 2023: 9 · 2022: 2 · 2021: 15 · 2020: 5 · 2019: 11 · 2018: 4 · 2017: 8 · 2016: 9 · 2015: 3
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Update notices
- correction (2014-11-24)
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Archivio Istituzionale della Ricerca - Università degli Studi del Molise (submittedVersion, cc-by)
- Iris (Roma Tre University) (submittedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- Rett syndrome, cholesterol metabolism, cholesterol homeostasis, MeCP2, dermal fibroblasts, plasma lipid profile, HMGR, SREBP, LDL receptor, scavenger receptor class B type I, PCSK9, lipid metabolism, X-linked disorders
- MeSH terms
- Proprotein Convertase 9, Adolescent, Adult, Animals, Cells, Cultured, Child, Child, Preschool, Cholesterol, Female, Fibroblasts, Humans, Hydroxymethylglutaryl CoA Reductases, Male, Mutation, Receptors, LDL, Serine Endopeptidases, Rett Syndrome, Case-Control Studies, Mice, Knockout, Proprotein Convertases, Scavenger Receptors, Class B, Mice, Sterol Regulatory Element Binding Proteins, Methyl-CpG-Binding Protein 2, Young Adult
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