Enhanced expression of the central survival of motor neuron (<scp>SMN</scp>) protein during the pathogenesis of osteoarthritis

Cucchiarini, Magali; Madry, Henning; Terwilliger, Ernest F.

doi:10.1111/jcmm.12170

Cited by 8 publications

(9 citation statements)

References 47 publications

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“…These lncRNAs are specific to humans and their expressions appear to downregulate SMN levels through transcriptional control. The significance of fine-tuning of SMN levels within cells is underscored by a recent study that showed the pathogenesis of osteoarthritis caused by aberrantly high expression of SMN [41]. Factors that regulate SMN transcription and splicing modulate SMN levels in a cell-specific manner.…”

Section: Organization Of Human Smn Genesmentioning

confidence: 99%

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Singh

2018

Advances in Neurobiology

112

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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: Organization Of Human Smn Genesmentioning

confidence: 99%

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Singh

2018

Advances in Neurobiology

112

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“…Based on the mislocalization of SMN and/or perturbations in SMN-associated functions, the role of SMN has been implicated in inclusion-body myositis and ALS [52,53]. In the case of osteoarthritis, SMN is expressed at an aberrantly high level in cartilage [54]. On the other hand, low SMN expression has been recently linked to testicular defects and male infertility [57].…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the role of SMN has been implicated in inclusion body myositis, amyotrophic lateral sclerosis (ALS) and osteoarthritis [52–54]. Supporting a role of SMN in mammalian testicular development and male fertility, its levels in testis are very high compared to other organs and tissues due in part to the predominant inclusion of exon 7 during SMN2 pre-mRNA splicing [55,56].…”

Section: Introductionmentioning

confidence: 99%

“…Consistently, under the condition of decreased SMN levels, male mice display defective testicular development, impaired spermatogenesis and reduced fertility [57]. Interestingly, an aberrant high SMN expression was recorded in osteoarthritis cartilage compared to the normal cartilage [54]. However, it remains to be seen if the high SMN expression in osteoarthritis cartilage is a cause or effect of osteoarthritis.…”

Section: Introductionmentioning

confidence: 99%

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Diverse role of survival motor neuron protein

Singh

Howell

Ottesen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

235

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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“…Interestingly, in the case of a recently reported osteoarthritis study, SMN is expressed at an aberrantly high level in cartilage. 68 Thus, increasing SMN protein too much could also negatively affect tissue homeostasis and function. This report suggests the need for therapeutic approaches that show high efficacy, even when they upregulate SMN only modestly.…”

Section: Discussionmentioning

confidence: 99%

Gender-Specific Amelioration of SMA Phenotype upon Disruption of a Deep Intronic Structure by an Oligonucleotide

et al. 2017

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Spinal muscular atrophy (SMA), the leading genetic disease of children, is caused by low levels of survival motor neuron (SMN) protein. Here, we employ A15/283, an antisense oligonucleotide targeting a deep intronic sequence/structure, to examine the impact of restoration of SMN in a mild SMA mouse model. We show gender-specific amelioration of tail necrosis upon subcutaneous administrations of A15/283 into SMA mice at postnatal days 1 and 3. We also demonstrate that a modest increase in SMN due to early administrations of A15/283 dramatically improves testicular development and spermatogenesis. Our results reveal near total correction of expression of several genes in adult testis upon temporary increase in SMN during early postnatal development. This is the first demonstration of in vivo efficacy of an antisense oligonucleotide targeting a deep intronic sequence/structure. This is also the first report of gender-specific amelioration of SMA pathology upon a modest peripheral increase of SMN.

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Enhanced expression of the central survival of motor neuron (SMN) protein during the pathogenesis of osteoarthritis

Cited by 8 publications

References 47 publications

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Diverse role of survival motor neuron protein

Gender-Specific Amelioration of SMA Phenotype upon Disruption of a Deep Intronic Structure by an Oligonucleotide

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