TY - JOUR T1 - An ALS-associated mutation in human FUS reduces neurotransmission from <em>C. elegans</em> motor neurons to muscles JF - bioRxiv DO - 10.1101/860536 SP - 860536 AU - Sebastian M. Markert AU - Michael Skoruppa AU - Bin Yu AU - Ben Mulcahy AU - Mei Zhen AU - Shangbang Gao AU - Michael Sendtner AU - Christian Stigloher Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/30/860536.abstract N2 - Amytrophic lateral sclerosis (ALS) is a neurodegenerative disorder that has been associated with multiple genetic lesions, including mutations in the gene FUS (Fused in Sarcoma), an RNA/DNA-binding protein. Expression of the ALS-associated human FUS in C. elegans results in mislocalization and aggregation of FUS outside the nucleus, and leads to impaired neuromuscular behaviors. However, the mechanisms by which mutant FUS disrupts neuronal health and function remain partially understood. Here we investigated the impact of ALS-associated FUS on motor neuron health using correlative light and electron microscopy, electron tomography, and electrophysiology. Expression of ALS-associated FUS impairs synaptic vesicle docking at neuromuscular junctions, and leads to the emergence of a population of large and electron-dense filament-filled endosomes. Electrophysiological recording of neuromuscular transmission revealed reduced transmission from motor neurons to muscles. Together, these results suggest a potential direct or indirect role of human FUS in the organization of synaptic vesicles, and reduced transmission from motor neurons to muscles.Summary statement An ALS-associated mutation in a trafficking protein disrupts the organization of the C. elegans neuromuscular junction. ER -