Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy

Kariya, Shingo; Park, Gyu-Hwan; Maeno-Hikichi, Yuka; Leykekhman, Olga; Lutz, Cathleen; Arkovitz, Marc S.; Landmesser, Lynn T.; Monani, Umrao R.

doi:10.1093/hmg/ddn156

Cited by 392 publications

(453 citation statements)

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“…Recent studies revealed NMJ defects as a characteristic feature of SMA pathology and potentially the cause of, or a contributor to, motor neuron death and muscle atrophy (Kariya et al 2008). Muscles are selectively affected, and one of the most vulnerable muscles in the SMND7 mouse model is the longissimus capitus, which shows ;28% fully denervated fibers in this slightly milder model at the end stage (P12-P14) ).…”

Section: Resultsmentioning

confidence: 99%

“…However, how suboptimal levels of SMN lead to SMA is largely unknown. Multiple studies in SMA mouse models revealed widespread synaptic defects in neuromuscular junctions (NMJs), including neurofilament accumulation, poor terminal arborization, immature endplates, reduced quantal content, disturbed calcium homeostasis, and decreased remodeling potential; these defects precede motor neuron death (Cifuentes-Diaz et al 2002;Le et al 2005;Jablonka et al 2007;Kariya et al 2008;Murray et al 2008Murray et al , 2012Kong et al 2009;Ling et al 2010;Ruiz et al 2010;Lee et al 2011), suggesting that the NMJ alterations are the initial consequence of SMN deficiency, Ó 2015 Hua et al This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http:// creativecommons.org/licenses/by-nc/4.0/.…”

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Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

et al. 2015

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Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in motor neurons only partially rescues SMA in mouse models, although it is thought to be therapeutically essential. Here, we address the relative importance of SMN restoration in the central nervous system (CNS) versus peripheral tissues in mouse models using a therapeutic spliceswitching antisense oligonucleotide to restore SMN and a complementary decoy oligonucleotide to neutralize its effects in the CNS. Increasing SMN exclusively in peripheral tissues completely rescued necrosis in mild SMA mice and robustly extended survival in severe SMA mice, with significant improvements in vulnerable tissues and motor function. Our data demonstrate a critical role of peripheral pathology in the mortality of SMA mice and indicate that peripheral SMN restoration compensates for its deficiency in the CNS and preserves motor neurons. Thus, SMA is not a cell-autonomous defect of motor neurons in SMA mice.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

et al. 2015

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“…Importantly, no consensus has been reached regarding the cellular and molecular pathways whose perturbation results in SMA pathology. Identifying the cellular pathways most sensitive to decreased SMN is essential to understand how SMN depletion causes neuronal dysfunction/death in SMA and to accelerate therapy development.One of the early events in SMA pathogenesis is the loss of neuromuscular junction (NMJ) function, evidenced by muscle denervation, neurofilament accumulation, and delayed neuromuscular maturation (25)(26)(27). In addition, reduced neurotransmitter release and decreased numbers of docked vesicles that precede axonal degeneration and/or motor neuron death have been reported at synapses of severe SMA mouse models (28,29).…”

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confidence: 99%

“…One of the early events in SMA pathogenesis is the loss of neuromuscular junction (NMJ) function, evidenced by muscle denervation, neurofilament accumulation, and delayed neuromuscular maturation (25)(26)(27). In addition, reduced neurotransmitter release and decreased numbers of docked vesicles that precede axonal degeneration and/or motor neuron death have been reported at synapses of severe SMA mouse models (28,29).…”

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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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