SMN Deficiency Causes Tissue-Specific Perturbations in the Repertoire of snRNAs and Widespread Defects in Splicing

Zhang, Zhenxi; Lotti, Francesco; Dittmar, Kimberly; Younis, Ihab; Wan, Lili; Kasim, Mumtaz; Dreyfuss, Gideon

doi:10.1016/j.cell.2008.03.031

Cited by 566 publications

(701 citation statements)

References 61 publications

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“…Several previous studies, including ours, have reported strong up-regulation of Cdkn1a/p21, a cyclin-dependent kinase inhibitor and mediator of cell cycle arrest downstream of p53, as well as other regulators of cell cycle and DNA repair in SMA models (6,19,(23)(24)(25). Whereas the Cdkn1a up-regulation has been attributed to a p53-independent stabilization of Cdkn1a transcript in the absence of SMN protein (26,27), few other gene expression changes can be explained by such posttranscriptional regulation.…”

Section: Significancementioning

confidence: 53%

“…Consistent with a fundamental role for SMN in snRNP assembly, Dreyfuss et al (19) identified distinct patterns of aberrant splicing by exon array analysis across several tissues of a severe mouse model of SMA and attributed these defects to tissue-specific alterations in snRNA levels. Presymptomatic SMA mice exhibit motor neuronspecific skipping of the agrin Z exons, which are involved in postsynaptic organization of acetylcholine receptors at the neuromuscular junction and may contribute to the NMJ defects seen in human patients (20).…”

Section: Significancementioning

confidence: 83%

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SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Jangi

Fleet

Cullen

et al. 2017

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

108

111

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Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of the broad functions of SMN leads to neurodegeneration remain unclear. We used an antisense oligonucleotide (ASO)-based inducible mouse model of SMA to investigate the SMN-specific transcriptome changes associated with neurodegeneration. We found evidence of widespread intron retention, particularly of minor U12 introns, in the spinal cord of mice 30 d after SMA induction, which was then rescued by a therapeutic ASO. Intron retention was concomitant with a strong induction of the p53 pathway and DNA damage response, manifesting as γ-H2A.X positivity in neurons of the spinal cord and brain. Widespread intron retention and markers of the DNA damage response were also observed with SMN depletion in human SH-SY5Y neuroblastoma cells and human induced pluripotent stem cell-derived motor neurons. We also found that retained introns, high in GC content, served as substrates for the formation of transcriptional R-loops. We propose that defects in intron removal in SMA promote DNA damage in part through the formation of RNA:DNA hybrid structures, leading to motor neuron death.

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Section: Significancementioning

confidence: 53%

Section: Significancementioning

confidence: 83%

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Jangi

Fleet

Cullen

et al. 2017

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

108

111

View full text Add to dashboard Cite

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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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“…Rabin et al [72] purified RNA from motor neurons that had been laser-dissected from the spinal cord of patients with sALS and demonstrated a significant enrichment of cellular adhesion genes in alternatively spliced transcripts. A similar pattern was observed in a mouse model of the motor neuron disease spinal muscular atrophy (SMA) [73], suggesting either that these differences might be a secondary phenomenon observed in association with neurodegeneration or that disrupted cell adhesion represents a conserved neurotoxic pathway in ALS and SMA. In support of the latter hypothesis, Sareen et al [66] also noted an enrichment of differentially expressed cellular adhesion genes in iPSC-derived neurons from patients with C9orf72 expansions.…”

Section: Rna Expressionmentioning

confidence: 55%

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Barmada

2015

Neurotherapeutics

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The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.

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SMN Deficiency Causes Tissue-Specific Perturbations in the Repertoire of snRNAs and Widespread Defects in Splicing

Cited by 566 publications

References 61 publications

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

SMN - A chaperone for nuclear RNP social occasions?

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

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