Proteasomal inhibition attenuates craniofacial malformations in a zebrafish model of Treacher Collins Syndrome.
Biochem Pharmacol
; 163: 362-370, 2019 05.
Article
en En
| MEDLINE
| ID: mdl-30849304
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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Fosfoproteínas
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Proteínas de Unión al ARN
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Regulación del Desarrollo de la Expresión Génica
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Proteínas de Pez Cebra
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Morfolinos
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Disostosis Mandibulofacial
Límite:
Animals
Idioma:
En
Revista:
Biochem Pharmacol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Argentina