Neuromuscular defects and breathing disorders in a new mouse model of spinal muscular atrophy

Michaud, Magali; Arnoux, Thomas; Bielli, Serena; Durand, Estelle; Rotrou, Yann; Jablonka, Sibylle; Robert, Fabrice; Giraudon-Paoli, Marc; Rießland, Markus; Mattei, Marie-Genevı̀eve; Andriambeloson, Emile; Wirth, Brunhilde; Sendtner, Michael; Gallego, Jorge; Pruss, Rebecca M.; Bordet, Thierry

doi:10.1016/j.nbd.2010.01.006

Cited by 69 publications

(62 citation statements)

References 49 publications

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“…Expectedly, SMN levels in 8-copy SMN2 Smn -/-mice were restored to near normal. In the years since this early work was reported, the strategy of exploiting the human SMN2 gene has been modified in subtle ways to generate a number of additional SMA model mice [62][63][64][65][66]. Their use, as described below, has not only led to novel insights into the cellular and molecular basis of the human disease, but has also served as a springboard for the design and development of promising therapies for the patient population.…”

Section: Sma: Novel Insights From Model Micementioning

confidence: 99%

Spinal Muscular Atrophy: Journeying From Bench to Bedside

2014

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Spinal muscular atrophy (SMA) is a frequently fatal neuromuscular disorder and the most common inherited cause of infant mortality. SMA results from reduced levels of the survival of motor neuron (SMN) protein. Although the disease was first described more than a century ago, a precise understanding of its genetics was not obtained until the SMA genes were cloned in 1995. This was followed in rapid succession by experiments that assigned a role to the SMN protein in the proper splicing of genes, novel animal models of the disease, and the eventual use of the models in the pre clinical development of rational therapies for SMA. These successes have led the scientific and clinical communities to the cusp of what are expected to be the first truly promising treatments for the human disorder. Yet, important questions remain, not the least of which is how SMN paucity triggers a predominantly neuromuscular phenotype. Here we review how our understanding of the disease has evolved since the SMA genes were identified. We begin with a brief description of the genetics of SMA and the proposed roles of the SMN protein. We follow with an examination of how the genetics of the disease was exploited to develop genetically faithful animal models, and highlight the insights gained from their analysis. We end with a discussion of ongoing debates, future challenges, and the most promising treatments to have emerged from our current knowledge of the disease.

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Section: Sma: Novel Insights From Model Micementioning

confidence: 99%

Spinal Muscular Atrophy: Journeying From Bench to Bedside

2014

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“…One group generated two SMN2 transgenic lines that harbor 1 or 2 copies of SMN2 per allele (lines N11 and N46). When combined to generate a 3 copy SMN2 mouse, the survival was extended to PND14-16 with some outlier longer lived mice (Michaud et al 2010). This average survival is similar to the SMN∆7 mice and is accompanied by severe muscle weakness and atrophy late in disease, motor neuron loss by PND13, abnormal EMG, and NMJ defects.…”

Section: Park 2010mentioning

confidence: 99%

“…Histological analyses of motor neuron populations in the spinal cord of SMA mouse models have demonstrated that the loss of motor neurons is also seen during the progression of the disease in mice. Surprisingly, the loss of motor neurons in the spinal cord is a late marker of disease, occurring after a motor deficit is already observed and late in disease progression (Hsieh-Li et al 2000;Jablonka et al 2000;Monani et al 2000;Monani et al 2003;Le et al 2005;Avila et al 2007;Kariya et al 2008;Bowerman et al 2009;Michaud et al 2010;. The development of motor neurons was thus further analysed in the most severe mice (Line 89) during embryonic and neonatal development.…”

Section: Neurological Manifestations In Sma Mouse Modelsmentioning

confidence: 99%

“…To evaluate the function of the motor neurons, both anatomical and electrophysiological analyses have been performed in severe and mild SMA mouse models. In severe and mild models of SMA, accumulation of neurofilament in the presynaptic termini of motor neurons, disorganization of the postsynaptic NMJ, reduced synaptic vesicle release, and motor neuron sprouting have been reported Monani et al 2003;Kariya et al 2008;McGovern et al 2008;Murray et al 2008;Kong et al 2009;Ling et al 2010;Michaud et al 2010;Lee et al 2011). The changes at the NMJ are also associated with expression of immature isoforms of both the acetylcholine receptor (AChR) and myosin heavy chain (MyHC) (Kariya et al 2008;Lee et al 2011).…”

Section: Neurological Manifestations In Sma Mouse Modelsmentioning

confidence: 99%

“…Defects in sensory neurons have been reported in SMA patients (Rudnik-Schoneborn et al 2003), and the 3 copy SMN2 mouse also exhibited latency in response to heat (Michaud et al 2010). The potential for sensory neuron malfunction in SMA was further evaluated in the SMN∆7 mouse model.…”

Section: Neurological Manifestations In Sma Mouse Modelsmentioning

confidence: 99%

See 2 more Smart Citations

Modeling Spinal Muscular Atrophy in Mouse: A Disease of Splicing, Stability, and Timing

Bebee¹,

Chandler²

2011

Advanced Understanding of Neurodegenerative Diseases

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Failure of lower motor neuron radial outgrowth precedes retrograde degeneration in a feline model of spinal muscular atrophy

Wakeling

Joussemet

Costiou

et al. 2012

J of Comparative Neurology

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Feline SMA is a fully penetrant, autosomal recessive lower motor neuron disease in domestic cats that clinically resembles human SMA Type III. A whole genome linkage scan identified a ~140 kilobase deletion that abrogates expression of LIX1, a novel SMA candidate gene of unknown function. To characterize the progression of feline SMA, we assessed pathological changes in muscle and spinal cord from 3 days of age to beyond onset of clinical signs. EMG analysis indicating denervation occurred between 10 and 12 weeks, with the first neurological signs occurring at the same time. CMAP amplitudes were significantly reduced in the soleus and extensor carpi radialis muscles at 8 to 11 weeks. Quadriceps femoris muscle fibers from affected cats appeared smaller at 10 weeks; by 12 weeks atrophic fibers were more prevalent than in age-matched controls. In affected cats, significant loss of L5 ventral root axons was observed at 12 weeks. By 21 weeks of age, affected cats had 40% fewer L5 motor axons than normal. There was no significant difference in total L5 soma number, even at 21 weeks; thus degeneration begins distal to the cell body and proceeds retrogradely. Morphometric analysis of L5 ventral roots and horns revealed that 4 weeks prior to axon loss, motor axons in affected cats failed to undergo radial enlargement, suggesting a role for the putative disease gene, LIX1, in radial growth of axons.

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Neuromuscular defects and breathing disorders in a new mouse model of spinal muscular atrophy

Cited by 69 publications

References 49 publications

Spinal Muscular Atrophy: Journeying From Bench to Bedside

Spinal Muscular Atrophy: Journeying From Bench to Bedside

Modeling Spinal Muscular Atrophy in Mouse: A Disease of Splicing, Stability, and Timing

Failure of lower motor neuron radial outgrowth precedes retrograde degeneration in a feline model of spinal muscular atrophy

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