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

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

Neurodevelopmental disorders with early-onset neurodegeneration are heterogenous rare diseases affecting small children and causing progressive loss of motor milestones and spasticity within the first years of life. Because of their rarity, the scarcity of specialized centers and pharmaceutical attention, the majority of these cases remain invisible and untreatable. A dramatic burden on patients, families and the healthcare system derives from it. A partial solution comes from the recent advancement of genetic sequencing that is unraveling potential genetic causes of previously unknown diseases. Several candidate genes involved in the control of the dynamic structure of the cellular architecture (cytoskeleton) are being associated to these diseases. Nevertheless, experimental approaches are needed which i) validate the pathogenic effect of the mutations and ii) study their deleterious impact on cellular and sub-cellular processes in the context of brain development. This is needed to impact on the search of targetable molecules and mechanisms likely generalizable also to other neurodegenerative conditions (i.e. those manifesting in adulthood). As proposed, my MSCA-IF project “INNERVATE” ( 844636) combined inter-sector expertise (i.e. molecular and developmental biology with clinical genetics) to generate disease models and advance our mechanistic understanding of the pathology. Our modeling in small fish embryo focused on a subset of these encephalopathies caused by gene perturbations recently identified within a larger sequencing effort of undiagnosed cases at the host institute (Ospedale pediatrico Bambino Gesù). Small and transparent fish (zebrafish) allow to observe embryogenesis (and its alterations) without need of invasive methods. By microscopy observation, molecular biology and biochemistry, their fast development allows us to determine morphogenesis, molecular and behavioral defects within short time. The data obtained so far establish the involvement of impaired motoneuron development and innervation in the disease. Neurobehavioral assays were established to quantitatively assess locomotor fitness decay and provide sharable resources that can be exploited for further research and pre-clinical applications.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз