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

Descripción del proyecto

Variantes genéticas raras asociadas con la neurodegeneración

Los microtúbulos (MT) forman parte del citoesqueleto de la célula y participan en procesos biológicos fundamentales como, por ejemplo, la división celular y el transporte de vesículas intracelulares. Datos nuevos revelan que los cofactores de la tubulina TBCE y TBCD, implicados en la dinámica de los MT, también pueden participar en la aparición temprana de neurodegeneración. En el proyecto INNERVATE, financiado con fondos europeos, se empleará el pez cebra como modelo para estudiar los mecanismos patógenos de TBCE y TBCD y su efecto en la fisiología encefálica. Sus científicos supervisarán en tiempo real el comportamiento de los MT y los procesos celulares en neuronas de pez cebra mutante para TBCE y TBCD. Los resultados proporcionarán información relevante sobre las variantes genéticas asociadas con la neurodegeneración.

Objetivo

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.