Investigating the functional impact of neurodegeneration-causing rare variants in the teleost model zebrafish

Descrizione del progetto

Varianti genetiche rare associate alla neurodegenerazione

I microtubuli fanno parte del citoscheletro della cellula e sono implicati in processi biologici chiave come la divisione cellulare e il traffico intracellulare di vescicole. Vi sono sempre più prove secondo le quali i cofattori della tubulina TBCE e TBCD, implicati nella dinamica dei microtubuli, possono essere coinvolti anche nella neurodegenerazione precoce. Il progetto INNERVATE, finanziato dall’UE, userà il danio zebrato come modello per studiare i meccanismi patogeni di TBCE e TBCD e l’impatto sulla fisiologia del cervello. Gli scienziati monitoreranno in tempo reale il comportamento dei microtubuli e i processi cellulari nei neuroni di danio zebra mutanti per TBCE e TBCD. I risultati forniranno importanti informazioni sulle varianti genetiche correlate alla neurodegenerazione.

Obiettivo

Circa 30 million people in Europe suffer from life-threatening rare diseases, which are poorly understood. This major societal burden forces patients into endless paths for a diagnosis often without cure. EU cooperation efforts between countries contribute to improve research and visibility of these diseases with a primary role of the ‘Ospedale pediatrico Bambino Gesù’ (OPBG, Italy). Here, via next generation sequencing technology, Dr. Tartaglia recently described new genetic variants, including some in the tubulin cofactors TBCE and TBCD which alter microtubules (MTs) dynamics (crucial for brain development and maintenance) and cause previously undescribed early onset neurodegeneration. Yet the underlying pathogenic mechanisms and impact on the brain physiology remain elusive. Given the difficulty to reproduce brain physiology in vitro and its general inaccessibility, a vertebrate model amenable to genetic and whole-brain in vivo investigation is necessary. With its rapid and transparent development and genetic and imaging tools improving continuously, the small teleost fish zebrafish is ideal. I will monitor live MTs behaviour and cellular processes (e.g. cell division, axons formation and innervation) in the precursor and mature neurons of zebrafish TBCE and TBCD mutants, focusing on motoneurons. To this aim, I will combine my expertise in fish neurobiology with the host’skills in human genetics (Dr. Tartaglia) and fish gene editing (Dr. Del Bene, France). In line with the current EU efforts, this work will advance our understanding on rare genetic variants causing neurodegeneration. Deciphering the role of MTs dynamics on brain physiology will be relevant also for common brain disorders and exome sequencing of undiagnosed patients will further contribute to a genotype-phenotype catalog. Via an intensive transfer of knowledge, the project will increase EU multi-disciplinary competence on rare disorders in general, providing new models for therapy development.