The effect of the DcpS inhibitor D156844 on the protective action of follistatin in mice with spinal muscular atrophy

Harris, Ashlee W.; Butchbach, Matthew E.R.

doi:10.1016/j.nmd.2015.05.008

Cited by 12 publications

(10 citation statements)

References 36 publications

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“…The rho kinase inhibitor Y-27632 ameliorates the phenotype of SMA mice independent of SMN expression (Bowerman et al, 2010). Follistatin increases the lifespan of SMNΔ7 SMA mice (Harris and Butchbach, 2015; Rose Jr et al, 2009). This recombinant protein does not increase SMN expression in vivo suggesting that its effects are independent of SMN (Rose Jr et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

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

Butchbach

Lumpkin

Harris

et al. 2016

Experimental Neurology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Butchbach

Lumpkin

Harris

et al. 2016

Experimental Neurology

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“…The effect of different classes of small cell permeable compounds has been examined on increasing levels of SMN protein by enhancing transcription that improve disease phenotype in mice with SMA. These compounds include quinazoline compounds (eg, RG3039) that function as inhibitors of RNA decapping enzyme (DcpS) [26][27][28] and have been shown to improve the disease phenotype, including the lifespan of mice with SMA in different SMA mouse models, severe SMAD7 model [29][30][31] and intermediate Smn 2B/model. 32 Benefits of RG3039 treatment were observed in the improvement of SMA phenotype, such as increase in the number of spinal motor neurons and increase in the number of SMNcontaining gems.…”

Section: Regulation Of Smn2 Gene Expressionmentioning

confidence: 99%

Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

et al. 2016

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Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA.

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“…The severity of SMA has so far indicated that there is a relatively short therapeutic window to achieve a maximal effect, however, adjunctive or combinatorial strategies may expand this window, thereby increasing the number and the types of patients that respond to drugs. (26)(27)(28)(29)(48)(49)(50)(51)(52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of spinal muscular atrophy

Villalón

Kline

Smith

et al. 2019

Human Molecular Genetics

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Spinal muscular atrophy (SMA) is a devastating infantile genetic disorder caused by the loss of survival motor neuron (SMN) protein that leads to premature death due to loss of motor neurons and muscle atrophy. The approval of an antisense oligonucleotide therapy for SMA was an important milestone in SMA research; however, effective next-generation therapeutics will likely require combinatorial SMN-dependent therapeutics and SMN-independent disease modifiers. A recent cross-disease transcriptomic analysis identified Stathmin-1 (STMN1), a tubulin-depolymerizing protein, as a potential disease modifier across different motor neuron diseases, including SMA. Here, we investigated whether viral-based delivery of STMN1 decreased disease severity in a well-characterized SMA mouse model. Intracerebroventricular delivery of scAAV9-STMN1 in SMA mice at P2 significantly increased survival and weight gain compared to untreated SMA mice without elevating Smn levels. scAAV9-STMN1 improved important hallmarks of disease, including motor function, NMJ pathology and motor neuron cell preservation. Furthermore, scAAV9-STMN1 treatment restored microtubule networks and tubulin expression without affecting tubulin stability. Our results show that scAAV9-STMN1 treatment improves SMA pathology possibly by increasing microtubule turnover leading to restored levels of stable microtubules. Overall, these data demonstrate that STMN1 can significantly reduce the SMA phenotype independent of restoring SMN protein and highlight the importance of developing SMN-independent therapeutics for the treatment of SMA.

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The effect of the DcpS inhibitor D156844 on the protective action of follistatin in mice with spinal muscular atrophy

Cited by 12 publications

References 36 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

Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of spinal muscular atrophy

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