Proteasomal inhibition attenuates craniofacial malformations in a zebrafish model of Treacher Collins Syndrome

ROSAS, MAUCO GIL; LORENZATTI, AGUSTÍN; PORCEL DE PERALTA, MAURO S.; CALCATERRA, NORA B.; COUX, GABRIELA

BIOCHEMICAL PHARMACOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2019 vol. 163 p. 362 - 370

0006-2952

Treacher Collins Syndrome (TCS) is a congenital disease characterized by defects in the craniofacial skeleton andabsence of mental alterations. Recently we modelled TCS in zebrafish (Danio rerio) embryos through the microinjectionof 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, wasdetected in lower levels (without changes in its mRNA expression) in TCS-like embryos. As previous reportssuggested 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 malformationsin TCS. Here we show that treatment with both proteasome inhibitors produced a robust craniofacialcartilage phenotype recovery. This recovery seems to be consequence of a decreased degradation of Cnbp in TCSlikeembryos. Critical TCS manifestations, such as neuroepithelial cell death and cell redox imbalance wereattenuated. Thus, proteasome inhibitors may offer an opportunity for TCS molecular and phenotypic manifestation?sprevention. Although further development of new safe inhibitors compatible with administration duringpregnancy is required, our results encourage this therapeutic approach.