Aberrant lung lipids cause respiratory impairment in a Mecp2-deficient mouse model of Rett syndrome
| Autor: | Monica J. Justice, Neeti Vashi, Cameron Ackerley, Martin Post |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
AcademicSubjects/SCI01140 0301 basic medicine Methyl-CpG-Binding Protein 2 Mice 0302 clinical medicine Respiratory system Lung Genetics (clinical) Mice Knockout General Medicine 3. Good health Phenotype medicine.anatomical_structure Disease Susceptibility General Article Metabolic Networks and Pathways Protein Binding medicine.drug congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Rett syndrome Hindbrain Biology MECP2 03 medical and health sciences Internal medicine mental disorders Rett Syndrome Genetics medicine Animals Nuclear Receptor Co-Repressor 1 Fluvastatin Molecular Biology Lipogenesis RNA Pulmonary Surfactants Lipid Metabolism medicine.disease nervous system diseases Disease Models Animal 030104 developmental biology Endocrinology Nuclear receptor Mutation Biomarkers 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Severe respiratory impairment is a prominent feature of Rett syndrome, an X-linked disorder caused by mutations in methyl CpG-binding protein 2 (MECP2). Despite MECP2’s ubiquitous expression, respiratory anomalies are attributed to neuronal dysfunction. Here, we show that neutral lipids accumulate in mouse Mecp2-mutant lungs, whereas surfactant phospholipids decrease. Conditional deletion of Mecp2 from lipid-producing alveolar epithelial 2 (AE2) cells causes aberrant lung lipids and respiratory symptoms, whereas deletion of Mecp2 from hindbrain neurons results in distinct respiratory abnormalities. Single-cell RNA sequencing of AE2 cells suggests lipid production and storage increase at the expense of phospholipid synthesis. Lipid production enzymes are confirmed as direct targets of MECP2-directed nuclear receptor co-repressor 1/2 transcriptional repression. Remarkably, lipid-lowering fluvastatin improves respiratory anomalies in Mecp2-mutant mice. These data implicate autonomous pulmonary loss of MECP2 in respiratory symptoms for the first time and have immediate impacts on patient care. |
| Databáze: | OpenAIRE |
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