Comprehensive Modeling of Spinal Muscular Atrophy in <i>Drosophila melanogaster</i>

Spring, Ashlyn M.; Raimer, Amanda C.; Hamilton, Christine D.; Schillinger, Michela J.; Matera, A. Gregory

doi:10.1101/394908

Cited by 5 publications

(16 citation statements)

References 71 publications

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“…41 The eclosion assay was carried out by adapting the reference protocol. 44 25-30 larvae from the first late-stage/ second early stage were placed in tubes containing standard fly food or supplemented food, and their development was complete.…”

Section: Lifespan and Eclosion Assaysmentioning

confidence: 99%

Inhibition of autophagy rescues muscle atrophy in a LGMDD2 Drosophila model

et al. 2021

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Section: Lifespan and Eclosion Assaysmentioning

confidence: 99%

Inhibition of autophagy rescues muscle atrophy in a LGMDD2 Drosophila model

et al. 2021

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“…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).…”

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confidence: 99%

Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster

Spring

Raimer

Hamilton

et al. 2019

Front. Mol. Neurosci.

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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 focused on the 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 14 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 14 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.

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“…Defects in SMN cause Spinal Muscular Atrophy (Lefebvre et al, 1995). Drosophila Smn has been characterized as a potential model for Spinal Muscular Atrophy (Raimer et al, 2020; Sen et al, 2011; Spring et al, 2019). Smn has also previously been implicated in PHP (Sen et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

Homeostatic depression shows heightened sensitivity to synaptic calcium

Yeates

Frank

2020

Preprint

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Synapses and circuits rely on homeostatic forms of regulation in order to transmit meaningful information. The Drosophila melanogaster neuromuscular junction (NMJ) is a well-studied synapse that shows robust homeostatic control of function. Most prior studies of homeostatic plasticity at the NMJ have centered on presynaptic homeostatic potentiation (PHP). PHP happens when postsynaptic muscle neurotransmitter receptors are impaired, triggering retrograde signaling that causes an increase in presynaptic neurotransmitter release. As a result, normal levels of evoked excitation are maintained. The counterpart to PHP at the NMJ is presynaptic homeostatic depression (PHD). Overexpression of the Drosophila vesicular glutamate transporter (VGlut) causes an increase in the amplitude of spontaneous events. PHD happens when the synapse responds to the challenge by decreasing quantal content during evoked neurotransmission, again, resulting in normal levels of postsynaptic excitation. We hypothesized that there may exist a class of molecules that affects both PHP and PHD. Impairment of any such molecule could hurt the ability of a synapse to respond to any significant homeostatic challenge. We conducted an electrophysiology-based screen for blocks of PHD. While we did not observe a block of PHD in the genetic conditions screened, we instead found loss-of-function conditions that led to excess depression, i.e., a substantial deficit in evoked amplitude when combined with VGlut overexpression. The conditions causing this phenotype included a double heterozygous loss-of-function condition for genes encoding the inositol trisphosphate receptor (IP3R, itpr) and ryanodine receptor (RyR). IP3Rs and RyRs gate calcium release from intracellular stores. Pharmacological agents targeting IP3R and RyR recapitulated the genetic losses of these factors, as did lowering calcium levels from other sources. Our data are consistent with the idea that some factors required for homeostatic potentiation are also required for the synapse to achieve appropriate levels of homeostatic depression. Loss of such factors may disorient compensatory plasticity signals.

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Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster

Cited by 5 publications

References 71 publications

Inhibition of autophagy rescues muscle atrophy in a LGMDD2 Drosophila model

Inhibition of autophagy rescues muscle atrophy in a LGMDD2 Drosophila model

Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster

Homeostatic depression shows heightened sensitivity to synaptic calcium

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