Transcriptional profiling of differentially vulnerable motor neurons at pre-symptomatic stage in the Smn 2b/- mouse model of spinal muscular atrophy

Murray, Lyndsay M.; Beauvais, Ariane; Gibeault, Sabrina; Courtney, Natalie L.; Kothary, Rashmi

doi:10.1186/s40478-015-0231-1

Cited by 68 publications

(119 citation statements)

References 61 publications

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“…Consistent with our findings, increased expression of known p53-regulated transcripts was recently reported in vulnerable SMA motor neurons from a milder mouse model of SMA (Murray et al, 2015) and in mice in which SMN deficiency was induced postnatally using antisense oligonucleotides (Jangi et al, 2017). However, no causal link between p53 activation and motor neuron death was demonstrated in SMA mice.…”

Section: Discussionsupporting

confidence: 92%

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

et al. 2017

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Summary The hallmark of spinal muscular atrophy (SMA) – an inherited disease caused by ubiquitous deficiency in the SMN protein – is the selective degeneration of subsets of spinal motor neurons. Here we show that cell-autonomous activation of p53 occurs in vulnerable but not resistant motor neurons of SMA mice at pre-symptomatic stages. Moreover, pharmacological or genetic inhibition of p53 prevents motor neuron death, demonstrating that induction of p53 signaling drives neurodegeneration. At late disease stages, however, nuclear accumulation of p53 extends to resistant motor neurons and spinal interneurons but is not associated with cell death. Importantly, we identify phosphorylation of serine 18 as a specific post-translational modification of p53 that exclusively marks vulnerable SMA motor neurons and provide evidence that amino-terminal phosphorylation of p53 is required for the neurodegenerative process. Our findings indicate that distinct events induced by SMN deficiency converge on p53 to trigger selective death of vulnerable SMA motor neurons.

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Section: Discussionsupporting

confidence: 92%

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

et al. 2017

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“…Previously, low levels of SMN have been linked to widespread changes in expression patterns, [121][122][123][124][125][126][127][128] but it is currently an open question as to how these changes might be linked to Cajal bodies. In addition, the mechanism by which these conformational changes in the nucleus affect the rest of the cell and which cellular components and processes are most severely affected has yet to be studied.…”

Section: Smn and Cajal Body Structurementioning

confidence: 99%

SMN - A chaperone for nuclear RNP social occasions?

2016

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Survival Motor Neuron (SMN) protein localizes to both the nucleus and the cytoplasm. Cytoplasmic SMN is diffusely localized in large oligomeric complexes with core member proteins, called Gemins. Biochemical and cell biological studies have demonstrated that the SMN complex is required for the cytoplasmic assembly and nuclear transport of Sm-class ribonucleoproteins (RNPs). Nuclear SMN accumulates with spliceosomal small nuclear (sn)RNPs in Cajal bodies, sub-domains involved in multiple facets of snRNP maturation. Thus, the SMN complex forms stable associations with both nuclear and cytoplasmic snRNPs, and plays a critical role in their biogenesis. In this review, we focus on potential functions of the nuclear SMN complex, with particular emphasis on its role within the Cajal body.

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“…The health of neurons in the spinal cord was thus demonstrated by measuring two transcripts for apoptosis, TNF receptor superfamily member 6 (fas) and phorbol-12-myristate-13-acetate-induced protein 1 (Pmaip1), which are dysregulated in the spinal cord of SMA mice (46). At PND7, spinal cords from unaffected littermates expressed significantly lower transcript levels of fas and Pmaip1 than spinal cords from SMA-affected pups (Fig.…”

Section: Pip6a-pmo Treatment Demonstrates Dose-dependent Phenotypicmentioning

confidence: 99%

Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

Hammond

Hazell

Shabanpoor

et al. 2016

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

167

129

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The development of antisense oligonucleotide therapy is an important advance in the identification of corrective therapy for neuromuscular diseases, such as spinal muscular atrophy (SMA). Because of difficulties of delivering single-stranded oligonucleotides to the CNS, current approaches have been restricted to using invasive intrathecal single-stranded oligonucleotide delivery. Here, we report an advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration. SMA results from reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein because of loss-of-function mutations in the SMN1 gene. Therapeutic splice-switching oligonucleotides (SSOs) modulate exon 7 splicing of the nearly identical SMN2 gene to generate functional SMN protein. Pip6a-PMO yields SMN expression at high efficiency in peripheral and CNS tissues, resulting in profound phenotypic correction at doses an order-of-magnitude lower than required by standard naked SSOs. Survival is dramatically extended from 12 d to a mean of 456 d, with improvement in neuromuscular junction morphology, down-regulation of transcripts related to programmed cell death in the spinal cord, and normalization of circulating insulin-like growth factor 1. The potent systemic efficacy of Pip6a-PMO, targeting both peripheral as well as CNS tissues, demonstrates the high clinical potential of peptide-PMO therapy for SMA.spinal muscular atrophy | survival motor neuron | antisense oligonucleotide | splice switching oligonucleotide | cell-penetrating peptide S pinal muscular atrophy (SMA), a leading genetic cause of infant mortality primarily due to lower motor neuron degeneration and progressive muscle weakness, results from loss of the ubiquitous survival motor neuron 1 gene (SMN1) (1, 2). Humans have a second nearly identical copy, SMN2, that differs from SMN1 by a crucial nucleotide transition within exon 7 leading to the predominant generation of an alternative exon 7-excluded transcript and only marginally functional protein (3-7). SMN2 therefore fails to compensate for loss of SMN1 unless sufficient copies are present to generate functional levels of full-length SMN protein (2).A rational, gene therapy-based approach for SMA uses singlestranded antisense splice-switching oligonucleotides (SSOs) to enhance SMN2 pre-mRNA exon 7 inclusion via steric block of splice regulatory pre-mRNA elements (8). Targeting the intron splice silencer N1 (ISS-N1) site within intron 7, by deletion or SSOmediated splice switching, improves exon 7 inclusion (9, 10). ISS-N1-targeted SSOs used to treat presymptomatic severely affected neonatal SMA mice, via systemic or intracerebroventricular administration, extend survival from 10 to >100 d (11, 12). Although SSO targeting to the CNS is essential, there is also evidence for a peripheral role for the SMN in SMA (13-24).Although SSO therapy is currently at an advanced stage of de...

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Transcriptional profiling of differentially vulnerable motor neurons at pre-symptomatic stage in the Smn 2b/- mouse model of spinal muscular atrophy

Cited by 68 publications

References 61 publications

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

SMN - A chaperone for nuclear RNP social occasions?

Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

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