Modélisations de maladies des motoneurones en utilisant le poisson zébré
Hereditary spastic paraplegias (HSP) are a group of heterogeneous neurodegenerative diseases affecting upper motor neurons, causing progressive gait dysfunction and more than 60 genes have been linked to this disease. On the other hand, amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disorder that affects both upper and lower motor neurons, leading to muscle atrophy with spasticity and death in two to five years due to respiratory failure. These two motor neuron disorders, while separate, share common genes and pathological mechanisms and as such, increasing our knowledge about their similarities and differences can help us have a better understanding of each of them individually. In order to study these two diseases, we used previously characterized zebrafish models and developed new ones to deepen our understanding of the pathophysiological mechanisms of HSP and ALS. In the first part of this thesis, we identified ER stress as a new pathological mechanism at play in HSP due to spastin loss-of-function and showed that ER stress modulators are able to rescue the locomotor phenotype. We also identified a new gene causative of HSP, CAPN1 (SPG76), provided in vivo validation of its loss-of-function pathogenicity and identified microtubule networks disorganization as one of the main defects. In the second part of this thesis, we generated several new zebrafish models to study ALS. Two transgenic lines expressing either a wild-type or a mutant TDP-43 protein under the control of an inducible promoter allowed us to recapitulate previous findings obtained with mRNA injections and identify transcriptomic changes due to the mutant protein that are in line with recent transcriptomic data obtained in mouse models. We also generated two new lines with knock-in of ALS-causative point mutations in the tardbp and fus zebrafish endogenous genes using the CRISPR/Cas9 technology. These results underscore the value of the zebrafish model to study motor neuron disorders and their pathophysiological mechanisms as well as open new therapeutic avenues.
stress RE TDP-43 FUS spastin CRISPR/Cas9 calpain 1 Amyotrophic lateral sclerosis hereditary spastic paraplegia zebrafish ER stress