SMN expression is required in motor neurons to rescue electrophysiological deficits in the SMNΔ7 mouse model of SMA

McGovern, Vicki L.; Iyer, Chitra C.; Arnold, W. David; Gombash, Sara E.; Zaworski, Phillip G.; Blatnik, Anton J.; Foust, Kevin D.; Burghes, Arthur H.M.

doi:10.1093/hmg/ddv283

Cited by 53 publications

(51 citation statements)

References 102 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Restoration of SMN solely in motor neuron or reduction of SMN solely in motor neurons does not markedly alter the survival of these animals (Martinez et al, 2012; McGovern et al, 2015). Furthermore, there is rescue of both electrophysiological activity and innervation status of skeletal muscle when replacing SMN solely in motor neurons (Martinez et al, 2012; McGovern et al, 2015). Thus, rescue of SMN levels in motor neurons does not correlate with survival.…”

Section: Discussionmentioning

confidence: 91%

Protective effects of butyrate-based compounds on a mouse model for spinal muscular atrophy

Butchbach

Lumpkin

Harris

et al. 2016

Experimental Neurology

Self Cite

View full text Add to dashboard Cite

Proximal spinal muscular atrophy (SMA) is a childhood-onset degenerative disease resulting from the selective loss of motor neurons in the spinal cord. SMA is caused by the loss of SMN1 (survival motor neuron 1) but retention of SMN2. The number of copies of SMN2 modifies disease severity in SMA patients as well as in mouse models, making SMN2 a target for therapeutics development. Sodium butyrate (BA) and its analogue (4PBA) have been shown to increase SMN2 expression in SMA cultured cells. In this study, we examined the effects of BA, 4PBA as well as two BA prodrugs—glyceryl tributyrate (BA3G) and VX563—on the phenotype of SMNΔ7 SMA mice. Treatment with 4PBA, BA3G and VX563 but not BA beginning at PND04 significantly improved the lifespan and delayed disease end stage, with administration of VX563 also improving the growth rate of these mice. 4PBA and VX563 improved the motor phenotype of SMNΔ7 SMA mice and prevented spinal motor neuron loss. Interestingly, neither 4PBA nor VX563 had an effect on SMN expression in the spinal cords of treated SMNΔ7 SMA mice; however, they inhibited histone deacetylase (HDAC) activity and restored the normal phosphorylation states of Akt and glycogen synthase kinase 3β, both of which are altered by SMN deficiency in vivo. These observations show that BA-based compounds with favourable pharmacokinetics ameliorate SMA pathology possibly by modulating HDAC and Akt signaling.

show abstract

Section: Discussionmentioning

confidence: 91%

Protective effects of butyrate-based compounds on a mouse model for spinal muscular atrophy

Butchbach

Lumpkin

Harris

et al. 2016

Experimental Neurology

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, whether or not MN deafferentation modifies cell death in SMA is not clear, and may, in fact, be a consequence of primary MN pathology [61,101,102]. In this regard, it has been recently reported that SMN deficiency results in intrinsic changes in the electrophysiological properties of MNs [103], and that replacement of SMN only in MNs is necessary and sufficient to restore the functional deficits of motor units [104]. These findings suggest that adequate levels of SMN in MNs are crucial to avoid the dysfunction and subsequent degeneration of MNs.…”

Section: Discussionmentioning

confidence: 99%

“…It appears that muscle and nerve may be independently affected by SMN deficiency [17,107], and muscle has only a minor impact on SMA pathogenesis. Indeed, several studies have reported that improvements in skeletal muscle and NMJ morphology and physiology, after SMN replacement in MNs, do not result in a significant increase in survival [61,82,101,104,108,109]. Moreover, it has been recently shown that low levels of SMN in muscle are sufficient for its normal function, and muscular replacement of SMN does not modify the lifespan of SMA [110].…”

Section: Discussionmentioning

confidence: 99%

Chronic Treatment with the AMPK Agonist AICAR Prevents Skeletal Muscle Pathology but Fails to Improve Clinical Outcome in a Mouse Model of Severe Spinal Muscular Atrophy

et al. 2016

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by spinal and brainstem motor neuron (MN) loss and skeletal muscle paralysis. Currently, there is no effective treatment other than supportive care to ameliorate the quality of life of patients with SMA. Some studies have reported that physical exercise, by improving muscle strength and motor function, is potentially beneficial in SMA. The adenosine monophosphate-activated protein kinase agonist 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) has been reported to be an exercise mimetic agent that is able to regulate muscle metabolism and increase endurance both at rest and during exercise. Chronic AICAR administration has been shown to ameliorate the dystrophic muscle phenotype and motor behavior in the mdx mouse, a model of Duchenne muscular dystrophy. Here, we investigated whether chronic AICAR treatment was able to elicit beneficial effects on motor abilities and neuromuscular histopathology in a mouse model of severe SMA (the SMNΔ7 mouse). We report that AICAR improved skeletal muscle atrophy and structural changes found in neuromuscular junctions of SMNΔ7 animals. However, although AICAR prevented the loss of glutamatergic excitatory synapses on MNs, this compound was not able to mitigate MN loss or the microglial and astroglial reaction occurring in the spinal cord of diseased mice. Moreover, no improvement in survival or motor performance was seen in SMNΔ7 animals treated with AICAR. The beneficial effects of AICAR in SMA found in our study are SMN-independent, as no changes in the expression of this protein were seen in the spinal cord and skeletal muscle of diseased animals treated with this compound.

show abstract

“…Few studies have focused on the role of the muscle, glial cells, and motoneurons themselves in the overall function of the motor units in SMA. Recently, the glial-specific restoration of SMN in mice with reduced SMN levels was found to be necessary to restore part of the motor unit function in a severe mouse model (59). In our study, peripheral administration of an ASO that rescues the SMA-like phenotypes of the NMJ and motor unit coincides with a better correction of SMN2 splicing in the muscle than in the spinal cord and to a greater increase of SMN protein in the heart than in the brain or the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Bogdanik

Osborne

Davis

et al. 2015

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

View full text Add to dashboard Cite

Clinical presentation of spinal muscular atrophy (SMA) ranges from a neonatal-onset, very severe disease to an adult-onset, milder form. SMA is caused by the mutation of the Survival Motor Neuron 1 (SMN1) gene, and prognosis inversely correlates with the number of copies of the SMN2 gene, a human-specific homolog of SMN1. Despite progress in identifying potential therapies for the treatment of SMA, many questions remain including how late after onset treatments can still be effective and what the target tissues should be. These questions can be addressed in part with preclinical animal models; however, modeling the array of SMA severities in the mouse, which lacks SMN2, has proven challenging. We created a new mouse model for the intermediate forms of SMA presenting with a delay in neuromuscular junction maturation and a decrease in the number of functional motor units, all relevant to the clinical presentation of the disease. Using this new model, in combination with clinical electrophysiology methods, we found that administering systemically SMN-restoring antisense oligonucleotides (ASOs) at the age of onset can extend survival and rescue the neurological phenotypes. Furthermore, these effects were also achieved by administration of the ASOs late after onset, independent of the restoration of SMN in the spinal cord. Thus, by adding to the limited repertoire of existing mouse models for type II/III SMA, we demonstrate that ASO therapy can be effective even when administered after onset of the neurological symptoms, in young adult mice, and without being delivered into the central nervous system.

show abstract

SMN expression is required in motor neurons to rescue electrophysiological deficits in the SMNΔ7 mouse model of SMA

Cited by 53 publications

References 102 publications

Protective effects of butyrate-based compounds on a mouse model for spinal muscular atrophy

Protective effects of butyrate-based compounds on a mouse model for spinal muscular atrophy

Chronic Treatment with the AMPK Agonist AICAR Prevents Skeletal Muscle Pathology but Fails to Improve Clinical Outcome in a Mouse Model of Severe Spinal Muscular Atrophy

Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Contact Info

Product

Resources

About