Periodic Reporting for period 2 - NeuroFish (Neurofilaments in Health and neurodegenerative diseases)
Periodo di rendicontazione: 2022-07-01 al 2023-12-31
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.
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.
With an innovative project on NFs in zebrafish, the first phase of the project was to constitute the team, create novel biological tools and develop methodologies in vivo.
During this period, our team, composed of experts in microscopy, zebrafish and cytoskeleton confirmed the high relevance and the great innovative aspect of our research program. In particular, we are generating different fluorescent and non-fluorescent reporter lines for NFs and performed substantial optical optimization to manipulate and acquire the live dynamics of NFs in a living organism. Our results show our capacity to monitor in space and time the various aspects of NF dynamics within a physiological environment. Moreover, adapting this development with new disease models, we have the capacity to study the process of NF aggregation and to expand our deciphering of NF dynamics in the context of neurodegenerative diseases.
During this period, our team, composed of experts in microscopy, zebrafish and cytoskeleton confirmed the high relevance and the great innovative aspect of our research program. In particular, we are generating different fluorescent and non-fluorescent reporter lines for NFs and performed substantial optical optimization to manipulate and acquire the live dynamics of NFs in a living organism. Our results show our capacity to monitor in space and time the various aspects of NF dynamics within a physiological environment. Moreover, adapting this development with new disease models, we have the capacity to study the process of NF aggregation and to expand our deciphering of NF dynamics in the context of neurodegenerative diseases.
In health, the live dynamics of NFs in a living organism is unknown. While the field uncovered the importance and dynamics of NFs in vitro and ex vivo in mice, our research project uses the zebrafish species to tackle the live behavior of the NF array, as well as its signaling in a physiological environment, where multiple tissues are inter-connected. Evidencing a high level of dynamics of NFs using our newly established NF reporter lines, we have the capacity to investigate the cell autonomous and non-cell autonomous events regulating NF behavior in space and time. Our efforts to adapt this knowledge to pathologies for which NFs are a genetic target will enable us to monitor, for the first time the process of aggregation in an animal and to evaluate the contribution of the environment. With the zebrafish as the model system, our research program has the ambition to use this knowledge to develop therapeutic screening and identify small molecules able to alleviate NF dysfunctions and positively impact disease onset and progression. Overall, our project brings innovation in the study of the biology of NFs, a key cytoskeletal network that has been shown to be critical for neuronal functions but for which little is known regarding its in vivo behavior and dysfunction in neurodegenerative diseases.