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ALS gene, C9orf72, loss of function Zebrafish model shows motor and synaptic defects

Butti, Zoe; Giacomotto, Jean et Patten, Shunmoogum A. . ALS gene, C9orf72, loss of function Zebrafish model shows motor and synaptic defects In: 11e European Zebrafish Meeting, 26-27 October 2020, virtuel.

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motoneurons causing muscular atrophy, paralysis and ultimately to death. To this day, no curative treatment exists. Understanding the physiopathological mechanisms will help develop new efficient treatments. In 2011, an expansion of a repetition of a hexanucleotide (GGGGCC) in the first intronic region of the C9orf72 gene has been discovered as the first genetic cause of ALS. To investigate the role of C9orf72 loss of function in ALS, we used synthetic micro-RNAs to specifically target the zebrafish C9orf72 gene (C9-miRNA) and have developed a stable zebrafish C9-miRNA line with reduced expression of C9orf72. Upon loss of function of C9orf72, we observed that zebrafish C9-miRNA mutants display severe motor deficits starting at 6 days postfertilization (6 dpf ) and a majority die premature as of 15 dpf. Analysis of the neuromuscular junctions using specific presynaptic and postsynaptic markers znp1 and alpha-bungarotoxin respectively, revealed a significant decrease in the number of synaptic contacts in the C9-miRNA mutant line at 6 dpf correlating with a decreased synaptic vesicles turnover. Among the few fishes that survived till adulthood, we observed a significant motoneuron and muscle atrophy. We are currently performing electrophysiology studies to characterize the synaptic defects. Altogether, our zebrafish C9-miRNA replicates aspects of ALS and we are investigating further the role of reduced C9orf72 in ALS pathogenesis

Type de document: Document issu d'une conférence ou d'un atelier
Informations complémentaires: Affiche scientifique P044
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 14 juill. 2021 15:42
Dernière modification: 14 juill. 2021 15:42
URI: https://espace.inrs.ca/id/eprint/11857

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