Nonmammalian Animal Models of Spinal Muscular Atrophy

O'Hern, Patrick J.; Garcia, Eric L.; Liang, Hao; Hart, Anne C.; Matera, A. Gregory; Beattie, Christine E.

doi:10.1016/b978-0-12-803685-3.00014-8

Cited by 13 publications

(15 citation statements)

References 168 publications

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“…In addition, this work also fills a more general need in the field, namely, the modeling of intermediate forms of SMA. In many model systems, there are few effective models of SMA Types II and III (Burghes et al, 2017; O’Hern et al, 2017). In mouse, the many attempts to generate such models have almost invariably produced animals that are either severely affected, or completely unaffected in terms of neuromuscular phenotype (Le et al, 2005; Osborne et al, 2012).…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster

Spring

Raimer

Hamilton

et al. 2019

Front. Mol. Neurosci.

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“…, 2010 ). Complete loss of SMN is lethal in all organisms investigated to date ( O’Hearn et al. , 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF^Slmb degron

Gray

Kaifer

Baillat

et al. 2018

MBoC

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“…Types II and III (Burghes et al, 2017;O'Hern et al, 2017). In mouse, the many attempts to 71 generate such models have almost invariably produced animals that are either severely 72 affected, or completely unaffected in terms of neuromuscular phenotype (Le et al, 2005;73 Osborne et al, 2012).…”

Section: Introduction 23mentioning

confidence: 99%

“…This work has provided evidence that SMN's functions are conserved. However, in the fly and other model organisms, including mouse, there are few effective models for intermediate forms of SMA (Burghes et al, 2017;O'Hern et al, 2017). Nearly all of the models are severe and involve developmental delays or arrests that complicate analysis, including transcriptomic profiling of pre-mRNA splicing changes and neuromuscular development and function (Winkler et al, 2005;McWhorter et al, 2008;Hammond et al, 2010;Garcia et al, 2013;Garcia et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster

Spring

Raimer

Hamilton

et al. 2018

Preprint

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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, fruitfly, 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.

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Nonmammalian Animal Models of Spinal Muscular Atrophy

Cited by 13 publications

References 168 publications

Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster

Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF^Slmb degron

Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster

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Nonmammalian Animal Models of Spinal Muscular Atrophy

Cited by 13 publications

References 168 publications

Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster

Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron

Comprehensive Modeling of Spinal Muscular Atrophy in Drosophila melanogaster

Contact Info

Product

Resources

About

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF^Slmb degron