RT Journal Article SR Electronic T1 Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster JF bioRxiv FD Cold Spring Harbor Laboratory SP 394908 DO 10.1101/394908 A1 Ashlyn M. Spring A1 Amanda C. Raimer A1 Christine D. Hamilton A1 Michela J. Schillinger A1 A. Gregory Matera YR 2018 UL http://biorxiv.org/content/early/2018/11/15/394908.abstract AB Spinal muscular atrophy (SMA) is a neurodegenerative disorder that affects motor neurons, primarily in young children. SMA is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene. SMN functions in the assembly of spliceosomal RNPs and is well conserved in many model systems including mouse, zebrafish, fruit fly, nematode, and fission yeast. Work in Drosophila has primarily focused on loss of SMN function during larval stages, primarily using null alleles or strong hypomorphs. A systematic analysis of SMA-related phenotypes in the context of moderate alleles that more closely mimic the genetics of SMA has not been performed in the fly, leading to debate over the validity and translational value of this model. We therefore examined fourteen Drosophila lines expressing SMA patient-derived missense mutations in Smn, with a focus on neuromuscular phenotypes in the adult stage. Animals were evaluated on the basis of organismal viability and longevity, locomotor function, neuromuscular junction structure, and muscle health. In all cases, we observed phenotypes similar to those of SMA patients, including progressive loss of adult motor function. The severity of these defects is variable, and forms a broad spectrum across the fourteen lines examined, recapitulating the full range of phenotypic severity observed in human SMA. This includes late-onset models of SMA, which have been difficult to produce in other model systems. The results provide direct evidence that SMA-related locomotor decline can be reproduced in the fly and support the use of patient-derived SMN missense mutations as a comprehensive system for modeling SMA.This work was supported by a grant from the USA National Institute of General Medical Sciences (NIGMS), R01-GM118636 (to A.G.M.). A.M.S. was supported by a Seeding Postdoctoral Innovators in Research and Education (SPIRE) fellowship from the National Institutes of Health (NIH), K12-GM000678 (to D.T. Lysle). We thank C.A. Frank for providing the C15 Gal4 driver line. Note, a version of this manuscript has been posted on a pre-print server (Spring et al. 2018, doi: https://doi.org/10.1101/394908).