Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

Ahmad, Saif; Bhatia, Kanchan; Kannan, Aannapoorna; Gangwani, Laxman

doi:10.4137/jen.s33122

Cited by 74 publications

(71 citation statements)

References 131 publications

(182 reference statements)

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“…The exon 7-skipped transcript generated by SMN2 codes for SMNΔ 7, a partially functional and unstable protein [15–17]. Loss of SMN1 creates SMN deficit, leading to spinal muscular atrophy (SMA), a major genetic disease of children and infants [18, 19]. Aberrant expression and/or localization of SMN have been associated with several other diseases, including amyotrophic lateral sclerosis (ALS), metabolic disorders, male infertility, and stress-associated disorders [14, 20–22].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Singh

2018

Advances in Neurobiology

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: Introductionmentioning

confidence: 99%

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Singh

2018

Advances in Neurobiology

113

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“…20 While the genetic etiology of the disease is well-established, the molecular role of SMN in the disease is largely unknown and is the topic of many reviews. [25][26][27][28][29][30][31][32][33][34] …”

Section: Cajal Bodies and Their Componentsmentioning

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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“…SMA is characterized by the degeneration of α-motor neurons in the spinal cord, leading to progressive muscle weakness followed by respiratory insufficiency [1, 2]. SMA is caused by low levels of Survival Motor Neuron (SMN) protein due to homozygous deletion or mutation of the SMN1 gene [3, 4].…”

Section: Introductionmentioning

confidence: 99%

ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy

Ottesen

2017

Translational Neuroscience

148

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Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA. Upon procuring exclusive license from the University of Massachussets Medical School in 2010, Ionis Pharmaceuticals (formerly ISIS Pharamaceuticals) began clinical development of Spinraza™ (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX), an antisense drug based on ISS-N1 target. Spinraza™ showed very promising results at all steps of the clinical development and was approved by US Food and Drug Administration (FDA) on December 23, 2016. Spinraza™ is the first FDA-approved treatment for SMA and the first antisense drug to restore expression of a fully functional protein via splicing correction. The success of Spinraza™ underscores the potential of intronic sequences as promising therapeutic targets and sets the stage for further improvement of antisense drugs based on advanced oligonucleotide chemistries and delivery protocols.

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Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

Cited by 74 publications

References 131 publications

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

SMN - A chaperone for nuclear RNP social occasions?

ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy

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