Correction of cilia structure and function alleviates multi-organ pathology in Bardet–Biedl syndrome mice
| Autor: | Bing Wang, Mandy M. Smith, Stefano Zanotti, Stephen L. Madden, Hervé Husson, Vijay Modur, Laurie A. Smith, Nikolay O. Bukanov, Thomas A. Natoli, Sarah Moreno, Tyler Picariello, Katherine W. Klinger, Brenda Richards, Hyejung Park, Cheng Zhu, Oxana Ibraghimov-Beskrovnaya, Ryan J. Russo |
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| Rok vydání: | 2020 |
| Předmět: |
AcademicSubjects/SCI01140
0301 basic medicine Retinal degeneration congenital hereditary and neonatal diseases and abnormalities Pathology medicine.medical_specialty Cellular differentiation Biology Ciliopathies Glycosphingolipids 03 medical and health sciences 0302 clinical medicine Bardet–Biedl syndrome Gangliosides Genetics medicine Animals Cilia Enzyme Inhibitors Bardet-Biedl Syndrome Molecular Biology Genetics (clinical) Mice Knockout Cilium Proteins Cell Differentiation General Medicine medicine.disease Phenotype Disease Models Animal Ciliopathy 030104 developmental biology Glucosyltransferases lipids (amino acids peptides and proteins) General Article Signal transduction 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Bardet–Biedl syndrome (BBS) is a pleiotropic autosomal recessive ciliopathy affecting multiple organs. The development of potential disease-modifying therapy for BBS will require concurrent targeting of multi-systemic manifestations. Here, we show for the first time that monosialodihexosylganglioside accumulates in Bbs2−/− cilia, indicating impairment of glycosphingolipid (GSL) metabolism in BBS. Consequently, we tested whether BBS pathology in Bbs2−/− mice can be reversed by targeting the underlying ciliary defect via reduction of GSL metabolism. Inhibition of GSL synthesis with the glucosylceramide synthase inhibitor Genz-667161 decreases the obesity, liver disease, retinal degeneration and olfaction defect in Bbs2−/− mice. These effects are secondary to preservation of ciliary structure and signaling, and stimulation of cellular differentiation. In conclusion, reduction of GSL metabolism resolves the multi-organ pathology of Bbs2−/− mice by directly preserving ciliary structure and function towards a normal phenotype. Since this approach does not rely on the correction of the underlying genetic mutation, it might translate successfully as a treatment for other ciliopathies. |
| Databáze: | OpenAIRE |
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