PUBLICATION
Proteasomal inhibition attenuates craniofacial malformations in a zebrafish model of Treacher Collins Syndrome
- Authors
- Rosas, M.G., Lorenzatti, A., de Peralta, M.S.P., Calcatera, N.B., Coux, G.
- ID
- ZDB-PUB-190309-6
- Date
- 2019
- Source
- Biochemical pharmacology 163: 362-370 (Journal)
- Registered Authors
- Keywords
- Bortezomib, Cnbp, Neurocristopathies, Ribosomopathies, Treacle
- MeSH Terms
-
- Animals
- Embryo, Nonmammalian/abnormalities
- Embryo, Nonmammalian/drug effects
- Gene Expression Regulation, Developmental/drug effects*
- Gene Knockdown Techniques
- Mandibulofacial Dysostosis/metabolism*
- Mandibulofacial Dysostosis/pathology
- Morpholinos/adverse effects*
- Phosphoproteins/genetics
- Phosphoproteins/metabolism*
- RNA-Binding Proteins/metabolism*
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 30849304 Full text @ Biochem. Pharmacol.
Citation
Rosas, M.G., Lorenzatti, A., de Peralta, M.S.P., Calcatera, N.B., Coux, G. (2019) Proteasomal inhibition attenuates craniofacial malformations in a zebrafish model of Treacher Collins Syndrome. Biochemical pharmacology. 163:362-370.
Abstract
Treacher Collins Syndrome (TCS) is a congenital disease characterized by defects in the craniofacial skeleton and absence of mental alterations. Recently we modelled TCS in zebrafish (Danio rerio) embryos through the microinjection of Morpholino® oligonucleotides blocking the translation of the ortholog of the main causative gene (TCOF1). We showed that Cnbp, a key cytoprotective protein involved in normal rostral head development, was detected in lower levels (without changes in its mRNA expression) in TCS-like embryos. As previous reports suggested that Cnbp is degraded through the proteasomal pathway, we tested whether proteasome inhibitors (MG132 and Bortezomib (Velcade®, Millennium laboratories)) were able to ameliorate cranial skeleton malformations in TCS. Here we show that treatment with both proteasome inhibitors produced a robust craniofacial cartilage phenotype recovery. This recovery seems to be consequence of a decreased degradation of Cnbp in TCS-like embryos. Critical TCS manifestations, such as neuroepithelial cell death and cell redox imbalance were attenuated. Thus, proteasome inhibitors may offer an opportunity for TCS molecular and phenotypic manifestation's prevention. Although further development of new safe inhibitors compatible with administration during pregnancy is required, our results encourage this therapeutic approach.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping