Oxidative Stress Triggers Body-Wide Skipping of Multiple Exons of the Spinal Muscular Atrophy Gene

Seo, Joonbae; Singh, Natalia N.; Ottesen, Eric W.; Sivanesan, Senthilkumar; Shishimorova, Maria; Singh, Ravindra

doi:10.1371/journal.pone.0154390

Cited by 43 publications

(39 citation statements)

References 85 publications

(102 reference statements)

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“…SMN2 exons 5 and 7 become highly susceptible to skipping under the conditions of oxidative stress, although skipping of SMN1 exon 5 is also enhanced by oxidative stress. A recent study examined the effect of paraquat, an oxidative-stress-causing agent, on splicing of various SMN2 exons in different tissues of a transgenic mouse model harboring SMN2 [120]. Findings of this study revealed tissue-specific effect of oxidative stress on splicing of various SMN2 exons.…”

Section: Alternative Splicing Of Other Smn Exonsmentioning

confidence: 94%

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Singh

2018

Advances in Neurobiology

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113

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Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1 due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes.

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Section: Alternative Splicing Of Other Smn Exonsmentioning

confidence: 94%

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Singh

2018

Advances in Neurobiology

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113

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“…[35][36][37] In addition, nutritional deficiency, oxidative stress, and hypoxia, partly attributed to gastrointestinal dysfunction, may cause widespread splicing alterations, including SMN2, and accelerate SMA progression. [38][39][40] How Low Levels of SMN Cause SMA Recent insights into the role of SMN within motor neurons have furthered our understanding of the implications of SMN deficiency. 41 The best characterized role of the SMN complex is in the assembly of Sm proteins (a distinctive family of RNA associated small proteins) onto small nuclear RNAs (snRNAs), forming small nuclear ribonucleoproteins (snRNPs), which are essential components of pre-mRNA splicing machinery in cells.…”

Section: Genetic and Environmental Insights Into Pathogenesismentioning

confidence: 99%

Emerging therapies and challenges in spinal muscular atrophy

Farrar

Park

Vucic

et al. 2017

Annals of Neurology

194

170

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Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease‐modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized. Therapeutic strategies in the pipeline are appraised, ranging from SMN1 gene replacement to modulation of SMN2 encoded transcripts, to neuroprotection, to an expanding repertoire of peripheral targets, including muscle. With the advent of preliminary trial data, it can be reasonably anticipated that the SMA treatment landscape will transform significantly. Advancement in presymptomatic diagnosis and screening programs will be critical, with pilot newborn screening studies underway to facilitate preclinical diagnosis. The development of disease‐modifying therapies will necessitate monitoring programs to determine the long‐term impact, careful evaluation of combined treatments, and further acceleration of improvements in supportive care. In advance of upcoming clinical trial results, we consider the challenges and controversies related to the implementation of novel therapies for all patients and set the scene as the field prepares to enter an era of novel therapies. Ann Neurol 2017;81:355–368

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“…However, the consequences of low SMN levels on the synthesis of various selenoproteins in different tissues have not yet been assessed. Human SBP2 generates multiple alternatively spliced transcripts under normal and oxidative stress conditions [49,208,209]. Future studies will determine if various SBP2 isoforms interact with the SMN-TGS1 complex differently with the implications for the trafficking and/or translation of specific selenoprotein mRNAs.…”

Section: Role Of Smn In Rna Metabolismmentioning

confidence: 99%

Diverse role of survival motor neuron protein

Singh

Howell

Ottesen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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249

194

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The multifunctional Survival Motor Neuron (SMN) protein is required for the survival of all organisms of the animal kingdom. SMN impacts various aspects of RNA metabolism through the formation and/or interaction with ribonucleoprotein (RNP) complexes. SMN regulates biogenesis of small nuclear RNPs, small nucleolar RNPs, small Cajal body-associated RNPs, signal recognition particles and telomerase. SMN also plays an important role in DNA repair, transcription, pre-mRNA splicing, histone mRNA processing, translation, selenoprotein synthesis, macromolecular trafficking, stress granule formation, cell signaling and cytoskeleton maintenance. The tissue-specific requirement of SMN is dictated by the variety and the abundance of its interacting partners. Reduced expression of SMN causes spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA displays a broad spectrum ranging from embryonic lethality to an adult onset. Aberrant expression and/or localization of SMN has also been associated with male infertility, inclusion body myositis, amyotrophic lateral sclerosis and osteoarthritis. This review provides a summary of various SMN functions with implications to a better understanding of SMA and other pathological conditions.

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Oxidative Stress Triggers Body-Wide Skipping of Multiple Exons of the Spinal Muscular Atrophy Gene

Cited by 43 publications

References 85 publications

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Emerging therapies and challenges in spinal muscular atrophy

Diverse role of survival motor neuron protein

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