Deletion of smn-1, the Caenorhabditis elegans ortholog of the spinal muscular atrophy gene, results in locomotor dysfunction and reduced lifespan

Briese, Michael; Esmaeili, Behrooz; Fraboulet, Sandrine; Burt, Emma; Christodoulou, Stefanos; Towers, Paula R.; Davies, Kay E.; Sattelle, David B.

doi:10.1093/hmg/ddn320

Cited by 89 publications

(134 citation statements)

References 28 publications

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“…3 A, B, and F). This is consistent with previous work showing that smn-1(ok355) animals have no overt defects in nervous system morphology and no motor neuron death (31). Puncta of the endocytic APT-4 (AP2 α-adaptin) were altered in intensity and number in smn-1(ok355) animals ( Fig.…”

Section: Significancesupporting

confidence: 92%

“…The pumping rates of smn-1 loss-of-function animals [smn-1(ok355)] are significantly reduced (P = 3e-12; Fig. 1B) (31,32). To confirm that the defects described here are caused by smn-1 loss, we generated a new smn-1 allele, smn-1(rt248), using CRISPR/Cas9-targeted mutagenesis (34,35).…”

Section: Significancementioning

confidence: 84%

“…Animals with a wildtype copy of the endogenous smn-1 gene are referred to herein as smn-1(+) and are used as controls. Diminished smn-1 function causes slow growth and larval lethality and impairs neuromuscular function in pharyngeal pumping during feeding (31,32) (Fig. 1A).…”

Section: Significancementioning

confidence: 99%

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Decreased function of survival motor neuron protein impairs endocytic pathways

Dimitriadi

Derdowski

Kalloo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death.endocytic trafficking | survival motor neuron | spinal muscular atrophy | C. elegans | infection S pinal muscular atrophy (SMA) is one of the most severe neuromuscular diseases of childhood, with an incidence of 1 in 10,000 live births and a high carrier frequency of roughly 1 in 40 Caucasians (1-3). SMA is caused by reduced levels of the ubiquitously expressed survival of motor neuron (SMN) protein and results in degeneration of α-spinal cord motor neurons, muscle weakness, and/or death. Two human genes encode the SMN protein, SMN1 and SMN2. SMA alleles arise at relatively high frequency due to small intrachromosomal de novo rearrangements including the SMN1 locus (4). Patients often carry homozygous SMN1 deletions, although missense and nonsense alleles exist (5). Multiple copies of SMN2 rarely compensate for loss of SMN1 due to a C > T nucleotide change in SMN2 exon 7 that perturbs pre-mRNA splicing and results in a truncated protein of diminished function and stability (SMNΔ7) (5-9).SMN has numerous roles and interacts with various proteins, yet it remains unclear which interactions are most pertinent to SMA pathogenesis. As a component of the Gemin complex, SMN is required for biogenesis of small nuclear ribonucleoprotein (snRNP) particles critical for pre-mRNA splicing (10-12). Furthermore, SMN is needed for stress granule formation (13,14), is found in RNP granules moving through neuronal processes, and is part of RNP complexes implicated in synaptic local translation (15)(16)(17)(18)(19)(20). Additional roles for SMN, in transcription (21), in the PTEN-mediated protein synthesis pathway (22), in translational control (23), and in cell proliferation/differentiation (24), have been described. Importantly, no consensus has been reached regarding the cellular and molecular pathways wh...

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Section: Significancesupporting

confidence: 92%

Section: Significancementioning

confidence: 84%

See 1 more Smart Citation

Decreased function of survival motor neuron protein impairs endocytic pathways

Dimitriadi

Derdowski

Kalloo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…However, when the maternal contribution becomes depleted, the smn-1 homozygotes become discernible from wild type larvae, displaying reduced size and length with a rapidly progressive decline in motor function (motility and pharyngeal pumping) followed by larval arrest. Interestingly, the mutant does not display a reduction in the number of cholinergic motor neurons [72].…”

Section: Spinal Muscular Atrophymentioning

confidence: 94%

“…SMN-1 is a 207 amino acid protein that is 36% identical to its human counterpart and it retains the in vitro capacity to bind to RNA and SMI-1 (Gemin2 homologue) [68,69,70]. SMN-1 has also been shown to interact with worm fibrillarin [68], a component of small nucleolar ribonucleoproteins involved in processing pre-mRNAs [64], and selfoligomerise via its C-terminal region [68], defects in which correlate with disease severity in humans [71] [68,72]. However, when the maternal contribution becomes depleted, the smn-1 homozygotes become discernible from wild type larvae, displaying reduced size and length with a rapidly progressive decline in motor function (motility and pharyngeal pumping) followed by larval arrest.…”

Section: Spinal Muscular Atrophymentioning

confidence: 99%

C. elegans models of neuromuscular diseases expedite translational research

Sleigh

Sattelle²

2010

Translational Neuroscience

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The nematode Caenorhabditis elegans is a genetic model organism and the only animal with a complete nervous system wiring diagram. With only 302 neurons and 95 striated muscle cells, a rich array of mutants with defective locomotion and the facility for individual targeted gene knockdown by RNA interference, it lends itself to the exploration of gene function at nerve muscle junctions. With approximately 60% of human disease genes having a C. elegans homologue, there is growing interest in the deployment of lowcost, high-throughput, drug screens of nematode transgenic and mutant strains mimicking aspects of the pathology of devastating human neuromuscular disorders. Here we explore the contributions already made by C. elegans to our understanding of muscular dystrophies (Duchenne and Becker), spinal muscular atrophy, amyotrophic lateral sclerosis, Friedreich’s ataxia, inclusion body myositis and the prospects for contributions to other neuromuscular disorders. A bottleneck to low-cost, in vivo, large-scale chemical library screening for new candidate therapies has been rapid, automated, behavioural phenotyping. Recent progress in quantifying simple swimming (thrashing) movements is making such screening possible and is expediting the translation of drug candidates towards the clinic.

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A large animal model of spinal muscular atrophy and correction of phenotype

Duqué

Arnold

Odermatt

et al. 2015

Annals of Neurology

121

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Objectives Spinal muscular atrophy (SMA) is caused by reduced levels of SMN which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides or scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness and the response of clinically relevant biomarkers. Methods Using intrathecal delivery of scAAV9 expressing a shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN) and electrophysiology measures and pathology were performed. Results Knockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography (EMG) indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimates (MUNE), like human SMA. Neuropathology showed loss of motoneurons and motor axons. Pre-symptomatic delivery of scAAV9-SMN prevented SMA symptoms indicating all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures and pathology. Interpretation High SMN levels are critical in postnatal motoneurons and reduction of SMN results in a SMA phenotype which is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration and abrogation of phenotype can be achieved even after symptom onset.

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Deletion of smn-1, the Caenorhabditis elegans ortholog of the spinal muscular atrophy gene, results in locomotor dysfunction and reduced lifespan

Cited by 89 publications

References 28 publications

Decreased function of survival motor neuron protein impairs endocytic pathways

Decreased function of survival motor neuron protein impairs endocytic pathways

C. elegans models of neuromuscular diseases expedite translational research

A large animal model of spinal muscular atrophy and correction of phenotype

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