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/2018/08/30/394908.abstract AB Spinal muscular atrophy (SMA) is a common neurodegenerative disorder that affects motor neurons, primarily in young children. SMA is caused by loss-of-function mutations in the Survival Motor Neuron 1 (SMN1) gene and a corresponding reduction in SMN protein levels. 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 melanogaster has focused on molecular and cellular functions of SMN, primarily using null alleles or strong hypomorphs. A systematic analysis of SMA-related phenotypes over a range of Smn alleles has not been performed in the fly. This has led to debate over the validity of Drosophila as a proper model for SMA. We therefore examined fourteen fly lines expressing single SMA patient-derived SMN missense mutations for defects in both the larval and adult stages. Animals were evaluated on the basis of organismal viability and longevity, locomotor function, neuromuscular junction structure and development, muscle health, and immune system function. In all cases, we observed phenotypes consistent with those found in human SMA patients. Severity of these defects is variable, and forms a broad spectrum across the fourteen lines examined. We assert that these fly lines constitute an effective model for SMA, recapitulating the full range of phenotypic severity observed in human SMA patients.Significance Statement Spinal Muscular Atrophy (SMA) is a neuromuscular disorder resulting from loss-of-function mutations in survival motor neuron 1 (SMN1). Disease severity forms a broad spectrum in SMA patients ranging from onset in utero to adulthood. This spectrum has proven difficult to reproduce in mammalian systems, including mouse, which typically model either severe or mild forms of SMA, missing intermediate forms. Here, we use Drosophila melanogaster to analyze an allelic series of SMA-causing missense mutations and systematically assess SMA-related phenotypes. We found strong concordance between human and Drosophila phenotypes across a wide spectrum of severity and evidence of evolutionarily conserved roles for SMN in immune regulation and neuromuscular health. These findings validate the fruitfly as an effective, comprehensive model for SMA.