The project aims to study the biology of Neurofilaments (NFs), that together with actin and microtubules constitute the cytoskeleton of the cell. NFs represent a major biomedical and societal challenge. Indeed, NFs are a universal biomarker for nerve injury and neurological diseases, as a result of the release of NF degradation products in body fluids. Thus, highly-sensitive measures of NF peptides are predictive of disease onset, progression and treatment response for various neurological conditions and trauma, which is crucial for personalized medicine by aiding clinical management and reducing the cost of clinical drug development. Considering the 9 million people currently living with a neurodegenerative disease, the burden and cost of these pathologies is extremely high in terms of distress and economically, with 800 billion euros spent per year only for brain diseases. Moreover, NFs are a major contributor or directly the cause of neurodegeneration in human. First, abnormal aggregation of NFs is a pathological hallmark for most neurodegenerative diseases, which once alleviated revealed spectacular benefit in disease onset and progression. Second, NFs are the genetic cause of several pathologies, including the Charcot-Marie-Tooth (CMT) disease, the most inherited neuropathy of the peripheral nervous system.
With a high fundamental and biomedical relevance, our knowledge of NF biology has been limited due to the biased view that NFs are static/useless and to technical challenges inherent of their apolar and insoluble nature. Using mouse and cellular models, the field revealed the importance of NFs in neuronal functions (mechano-resistance, radial axonal outgrowth, microtubule regulation, organelle distribution and neurotransmission) and unexpected dynamics in their transport and degradation along the nerve. In disease, very little is known about the process of aggregation and what drives neurodegeneration. The overall objectives of this project are to use the zebrafish species to pioneer in scrutinizing, at a physiological level the dynamics of NFs in health, to push further our understanding of NF biology and develop therapy for NF-aggregate prone neurodegenerative diseases.
