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Reduced levels of\n                    <jats:italic>C9orf72<\/jats:italic>\n                    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\n                    <jats:italic>C9orf72<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s42003-021-02302-y","type":"journal-article","created":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T06:03:07Z","timestamp":1624600987000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish"],"prefix":"10.1038","volume":"4","author":[{"given":"Zo\u00e9","family":"Butti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingzhou Edward","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Giacomotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2782-3547","authenticated-orcid":false,"given":"Shunmoogum A.","family":"Patten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,25]]},"reference":[{"key":"2302_CR1","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","volume":"72","author":"M DeJesus-Hernandez","year":"2011","unstructured":"DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245\u2013256 (2011).","journal-title":"Neuron"},{"key":"2302_CR2","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.neuron.2011.09.010","volume":"72","author":"AE Renton","year":"2011","unstructured":"Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257\u2013268 (2011).","journal-title":"Neuron"},{"key":"2302_CR3","doi-asserted-by":"publisher","first-page":"E4968","DOI":"10.1073\/pnas.1315438110","volume":"110","author":"T Zu","year":"2013","unstructured":"Zu, T. et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc. Natl Acad. Sci. USA 110, E4968\u2013E4977 (2013).","journal-title":"Proc. Natl Acad. Sci. 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