| First Author | Husson H | Year | 2020 |
| Journal | Hum Mol Genet | Volume | 29 |
| Issue | 15 | Pages | 2508-2522 |
| PubMed ID | 32620959 | Mgi Jnum | J:296033 |
| Mgi Id | MGI:6456027 | Doi | 10.1093/hmg/ddaa138 |
| Citation | Husson H, et al. (2020) Correction of cilia structure and function alleviates multi-organ pathology in Bardet-Biedl syndrome mice. Hum Mol Genet 29(15):2508-2522 |
| abstractText | 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. |
