ZErareBRAL: ZEbrafish in vivo investigation of the fundamental role of Golgi dysfunction in the pathogenesis of a new class of rare cereBRAL malformations

Patients affected by rare neurodevelopmental diseases showing microcephaly, intellectual disability and untreatable epilepsy undergo unsuccessful diagnostic ordeals and lack curative therapies: a healthcare emergency at the core of EU priorities. Genetic sequencing and counseling can now improve diagnosis and alleviate patients’ invisibility. However, the scarce knowledge on many of the emerging genetic causes leaves a gap between disease identification and cure. Within an international program addressing undiagnosed patients, our team recently identified a new condition with microcephaly and epilepsy caused by mutations in the ARF3 gene, variably affecting the integrity and activity of a tiny cellular organelle, the Golgi, crucial to respond to increasing cell demands during brain development. The use of small zebrafish embryos highlighted Golgi-specific signatures linked to brain defects predictive of neurological outcomes and useful for patients’screening and diagnosis.

I propose to use advanced microscopy and sequencing technologies in transparent fish models, allowing entire brain investigation live, to study the pathomechanisms by which Golgi dysfunction impacts neural stem cells proliferation and destiny. The results made accessible to relevant stakeholders will be useful for evaluating the use of existing “off label” drugs. The project will also identify distinctive targets and establish neurobehavioral readouts to measure patient-specific epileptogenic susceptibility with the potential to attract industries’ interest for therapy development and large-scale drug screening. A larger impact of the results is expected considering that Golgi dysfunction is an early sign of neurodegeneration, congenital microcephaly caused by Zika virus and a potential target in novel experimental therapeutic protocols even in cancer