A critical smn threshold in mice dictates onset of an intermediate spinal muscular atrophy phenotype associated with a distinct neuromuscular junction pathology

Bowerman, Mélissa; Murray, Lyndsay M.; Beauvais, Ariane; Pinheiro, Bruno Botelho; Kothary, Rashmi

doi:10.1016/j.nmd.2011.09.007

Cited by 122 publications

(170 citation statements)

References 37 publications

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“…This is reminiscent of the absence of perforation of the endplates in the 2B/-model (20). At the molecular level, postsynaptic maturation delay was also observed in more severe SMA models and consisted in the abnormal persistence after birth of embryonic (type gamma) AChR subunits at the NMJ (49).…”

Section: Discussionmentioning

confidence: 83%

“…The Smn2B/-mouse model (20) and the SMN-read-through model (21) have a mean survival of 28-34 d. Milder SMA phenotypes have also been modeled by using selective ablation of SMN expression in critical tissues such as the skeletal muscle or the nervous system (22)(23)(24). These mouse mutants, with a median survival of 25 d, proved unequivocally that SMN is required in both the skeletal muscle and the motor neuron for the development of functional motor units.…”

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confidence: 99%

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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.

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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.

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Section: Discussionmentioning

confidence: 83%

mentioning

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.

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“…26,27 Moreover, defects in motor neuron axon outgrowth and path finding as well as decrease in the growth cone area, have been observed in different SMA animal models and cell cultures. [28][29][30] All these processes are connected with disturbances in the regulation of actin filament polymerization and disassembly performed by actin-binding proteins.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity

et al. 2013

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Spinal muscular atrophy (SMA) is a monogenic disorder that is subdivided into four different types and caused by survival motor neuron gene 1 (SMN1) deletion. Discordant cases of SMA suggest that there exist additional severity modifying factors, apart from the SMN2 gene copy number. Here we performed the first genome-wide methylation profiling of SMA patients and healthy individuals to study the association of DNA methylation status with the severity of the SMA phenotype. We identified strong significant differences in methylation level between SMA patients and healthy controls in CpG sites close to the genes CHML, ARHGAP22, CYTSB, CDK2AP1 and SLC23A2. Interestingly, the CHML and ARHGAP22 genes are associated with the activity of Rab and Rho GTPases, which are important regulators of vesicle formation, actin dynamics, axonogenesis, processes that could be critical for SMA development. We suggest that epigenetic modifications may influence the severity of SMA and that these novel genetic positions could prove to be valuable biomarkers for the understanding of SMA pathogenesis.

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“…18,[53][54][55][56] We aimed to test a situation suitable for future patient care and chose oral application beginning on the first day of life (P0). Protein analysis of SMA animals at different disease stages demonstrates that there may be organ as well as time-dependent effects of HDACi treatment on SMN levels.…”

Section: Discussionmentioning

confidence: 99%

Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

et al. 2012

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Spinal muscular atrophy (SMA) is the leading genetic cause of early childhood death worldwide and no therapy is available today. Many drugs, especially histone deacetylase inhibitors (HDACi), increase SMN levels. As all HDACi tested so far only mildly ameliorate the SMA phenotype or are unsuitable for use in humans, there is still need to identify more potent drugs. Here, we assessed the therapeutic power of the pan-HDACi JNJ-26481585 for SMA, which is currently used in various clinical cancer trials. When administered for 64 h at 100 nM, JNJ-26481585 upregulated SMN levels in SMA fibroblast cell lines, including those from non-responders to valproic acid. Oral treatment of Taiwanese SMA mice and control littermates starting at P0 showed no overt extension of lifespan, despite mild improvements in motor abilities and weight progression. Many treated and untreated animals showed a very rapid decline or unexpected sudden death. We performed exploratory autopsy and histological assessment at different disease stages and found consistent abnormalities in the intestine, heart and lung and skeletal muscle vasculature of SMA animals, which were not prevented by JNJ-26481585 treatment. Interestingly, some of these features may be only indirectly caused by a-motoneuron function loss but may be major life-limiting factors in the course of disease. A better understanding of -primary or secondary -non-neuromuscular organ involvement in SMA patients may improve standard of care and may lead to reassessment of how to investigate SMA patients clinically.

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A critical smn threshold in mice dictates onset of an intermediate spinal muscular atrophy phenotype associated with a distinct neuromuscular junction pathology

Cited by 122 publications

References 37 publications

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

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

Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity

Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

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