Correction of cilia structure and function alleviates multi-organ pathology in Bardet-Biedl syndrome mice.
Animals
Bardet-Biedl Syndrome
/ drug therapy
Cell Differentiation
/ drug effects
Cilia
/ genetics
Ciliopathies
/ drug therapy
Disease Models, Animal
Enzyme Inhibitors
/ pharmacology
Gangliosides
/ biosynthesis
Glucosyltransferases
/ antagonists & inhibitors
Glycosphingolipids
/ biosynthesis
Mice, Knockout
Proteins
/ genetics
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
29 08 2020
29 08 2020
Historique:
received:
15
05
2020
revised:
22
06
2020
accepted:
01
07
2020
pubmed:
6
7
2020
medline:
31
8
2021
entrez:
5
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32620959
pii: 5867075
doi: 10.1093/hmg/ddaa138
pmc: PMC7471507
doi:
Substances chimiques
Bbs2 protein, mouse
0
Enzyme Inhibitors
0
Gangliosides
0
Glycosphingolipids
0
Proteins
0
sialogangliosides
0
Glucosyltransferases
EC 2.4.1.-
ceramide glucosyltransferase
EC 2.4.1.80
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2508-2522Informations de copyright
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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