Distinct and overlapping alterations in motor and sensory neurons in a mouse model of spinal muscular atrophy

Jablonka, Sibylle; Karle, Kathrin N.; Sandner, Beatrice; Andreassi, Catia; Au, Katja von; Sendtner, Michael

doi:10.1093/hmg/ddi467

Cited by 73 publications

(67 citation statements)

References 27 publications

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“…Interestingly, Jablonka et al (Jablonka et al, 2006) recently reported that sensory neuron terminals in the footpads of SMN2 +/+ ;mSmn −/− (severe SMA) embryos are smaller. The difference in sensory neuron terminal size observed in severe SMA embryos is smaller the difference in motor neuron terminal size.…”

Section: Discussionmentioning

confidence: 99%

Abnormal motor phenotype in the SMNΔ7 mouse model of spinal muscular atrophy

Butchbach

Edwards

Burghes

2007

Neurobiology of Disease

123

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Spinal muscular atrophy (SMA) is recessive motor neuron disease that affects motor neurons in the anterior horn of the spinal cord. SMA results from the reduction of SMN (survival motor neuron) protein. Even though SMN is ubiquitously expressed, motor neurons are more sensitive to the reduction in SMN than other cell types. We have previously generated mouse models of SMA with varying degrees of clinical severity. So as to more clearly understand the pathogenesis of motor neuron degeneration in SMA, we have characterized the phenotype of the SMNΔ7 SMA mouse which normally lives for 13.6 ± 0.7 days. These mice are smaller than their non-SMA littermates and begin to lose body mass at 10.4 ± 0.4 days. SMNΔ7 SMA mice exhibit impaired responses to surface righting, negative geotaxis and cliff aversion but not to tactile stimulation. Spontaneous motor activity and grip strength are also significantly impaired in SMNΔ7 SMA mice. In summary, we have demonstrated an impairment of neonatal motor responses in SMNΔ7 SMA mice. This phenotype characterization could be used to assess the effectiveness of potential therapies for SMA.

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Section: Discussionmentioning

confidence: 99%

Abnormal motor phenotype in the SMNΔ7 mouse model of spinal muscular atrophy

Butchbach

Edwards

Burghes

2007

Neurobiology of Disease

123

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“…Smn-/-;SMN2 mice, a model for type I SMA, show no loss of L5 DRG neurons at the time of severe paralysis; however, nerve endings in the skin are thinner and unlike controls do not reach the outer epidermal layer [36] . In addition, cultured sensory neurons from these mice have shorter neurites, smaller growth cones, and decreased ␤ -actin protein and mRNA in the distal axon.…”

Section: Involvement Of Sensory Axonsmentioning

confidence: 98%

Axonal Degeneration in Motor Neuron Disease

Fischer¹,

Glass

2007

Neurodegener Dis

125

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Growing evidence from animal models and patients with amyotrophic lateral sclerosis (ALS) suggests that distal axonal degeneration begins very early in this disease, long before symptom onset and motor neuron death. The cause of axonal degeneration is unknown, and may involve local axonal damage, withdrawal of trophic support from a diseased cell body, or both. It is increasingly clear that axons are not passive extensions of their parent cell bodies, and may die by mechanisms independent of cell death. This is supported by studies in which protection of motor neurons in models of ALS did not significantly improve symptoms or prolong lifespan, likely due to a failure to protect axons. Here, we will review the evidence for early axonal degeneration in ALS, and discuss possible mechanisms by which it might occur, with a focus on oxidative stress. We contend that axonal degeneration may be a primary feature in the pathogenesis of motor neuron disease, and that preventing axonal degeneration represents an important therapeutic target that deserves increased attention.

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“…In severely affected neonates sensory and motor nerves may become inexcitable [8]. Axonal degeneration of sural nerves, posterior roots, spinal ganglia, ascending tracts, lateral geniculate corpus and thalamus have been reported [40,43], suggesting that the pathology predominates in but is not confined to the motor neurons.…”

Section: Diagnostic Evaluationmentioning

confidence: 99%

Spinal Muscular Atrophy: Molecular Mechanisms

Farrar

Johnston²,

Grattan-Smith³

et al. 2009

CMM

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Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder characterised by muscle weakness and atrophy due to degeneration of motor neurons of the spinal cord and cranial motor nuclei. The clinical phenotype incorporates a wide spectrum. No effective treatment is currently available and patients may experience severe physical disability which is often life limiting. The most common type of SMA is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene by deletion, conversion or mutation and results in insufficient levels of survival motor neuron (SMN) protein in motor neurons. While diagnosis is usually achieved by genetic testing, an illustrative clinical case is described that highlights the molecular and diagnostic complexities. While there is an emerging picture concerning the function of the SMN protein and the molecular pathophysiological mechanisms underpinning the disease, a number of substantial issues remain unresolved. The selective vulnerability of the motor neuron and the site and timing of the primary pathogenesis are not yet determined. Utilising the organisation of the SMN genomic region, recent advances have identified a number of potential therapeutic targets. As such, this review incorporates discussion of the clinical manifestations, molecular genetics, diagnosis, mechanisms of disease pathogenesis and development of novel treatment strategies.

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Distinct and overlapping alterations in motor and sensory neurons in a mouse model of spinal muscular atrophy

Cited by 73 publications

References 27 publications

Abnormal motor phenotype in the SMNΔ7 mouse model of spinal muscular atrophy

Abnormal motor phenotype in the SMNΔ7 mouse model of spinal muscular atrophy

Axonal Degeneration in Motor Neuron Disease

Spinal Muscular Atrophy: Molecular Mechanisms

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