PUBLICATION
Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish
- Authors
- Butti, Z., Pan, Y.E., Giacomotto, J., Patten, S.A.
- ID
- ZDB-PUB-210629-13
- Date
- 2021
- Source
- Communications biology 4: 792 (Journal)
- Registered Authors
- Giacomotto, Jean, Patten, Shumoogum
- Keywords
- none
- MeSH Terms
-
- Amyotrophic Lateral Sclerosis/etiology
- Animals
- C9orf72 Protein/physiology*
- Frontotemporal Dementia/etiology
- Neuromuscular Junction Diseases/etiology*
- Synaptic Vesicles/physiology*
- Zebrafish
- PubMed
- 34172817 Full text @ Commun Biol
Citation
Butti, Z., Pan, Y.E., Giacomotto, J., Patten, S.A. (2021) Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish. Communications biology. 4:792.
Abstract
The most common genetic cause of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) is a hexanucleotide repeat expansion within the C9orf72 gene. Reduced levels of C9orf72 mRNA and protein have been found in ALS/FTD patients, but the role of this protein in disease pathogenesis is still poorly understood. Here, we report the generation and characterization of a stable C9orf72 loss-of-function (LOF) model in the zebrafish. We show that reduced C9orf72 function leads to motor defects, muscle atrophy, motor neuron loss and mortality in early larval and adult stages. Analysis of the structure and function of the neuromuscular junctions (NMJs) of the larvae, reveal a marked reduction in the number of presynaptic and postsynaptic structures and an impaired release of quantal synaptic vesicles at the NMJ. Strikingly, we demonstrate a downregulation of SV2a upon C9orf72-LOF and a reduced rate of synaptic vesicle cycling. Furthermore, we show a reduced number and size of Rab3a-postive synaptic puncta at NMJs. Altogether, these results reveal a key function for C9orf72 in the control of presynaptic vesicle trafficking and release at the zebrafish larval NMJ. Our study demonstrates an important role for C9orf72 in ALS/FTD pathogenesis, where it regulates synaptic vesicle release and neuromuscular functions.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping