Faculty Opinions recommendation of Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA).

Spinal muscular atrophy (SMA) is a neurodegenerative disorder that is characterized by progressive loss of motor neuron function. It is caused by the homozygous loss of the SMN1 ( survival of motor neuron 1) gene and a decrease in full-length SMN protein. SMN2 is a nearly identical homolog of SMN1 that, due to alternative splicing, expresses predominantly truncated SMN protein. SMN2 represents an enticing therapeutic target. Increasing expression of full-length SMN from the SMN2 gene might represent a treatment for SMA. We describe a newly designed cell-based reporter assay that faithfully and reproducibly measures full-length SMN expression from the SMN2 gene. This reporter can detect increases of SMN protein by an array of compounds previously shown to regulate SMN2 expression and by the overexpression of proteins that modulate SMN2 splicing. It also can be used to evaluate changes at both the transcriptional and splicing level. This assay can be a valuable tool for the identification of novel compounds that increase SMN2 protein levels and the optimization of compounds already known to modulate SMN2 expression. We present here preliminary data from a high-throughput screen using this assay to identify novel compounds that increase expression of SMN2.

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Newborn Screening for Spinal Muscular Atrophy by Calibrated Short-Amplicon Melt Profiling

Clinical Chemistry ◽

10.1373/clinchem.2012.183038 ◽

2012 ◽

Vol 58 (6) ◽

pp. 1033-1039 ◽

Cited By ~ 24

Author(s):

Steven F Dobrowolski ◽

Ha T Pham ◽

Frances Pouch Downes ◽

Thomas W Prior ◽

Edwin W Naylor ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Newborn Screening ◽

Motor Neuron ◽

Muscular Atrophy ◽

Dried Blood Spots ◽

Continuous Treatment ◽

Management Options ◽

Blood Spots ◽

Survival Of Motor Neuron ◽

Homozygous Deletions

Abstract BACKGROUND The management options for the autosomal recessive neurodegenerative disorder spinal muscular atrophy (SMA) are evolving; however, their efficacy may require presymptom diagnosis and continuous treatment. To identify presymptomatic SMA patients, we created a DNA-based newborn screening assay to identify the homozygous deletions of the SMN1 (survival of motor neuron 1, telomeric) gene observed in 95%–98% of affected patients. METHODS We developed primers that amplify a 52-bp PCR product from homologous regions in the SMN1 and SMN2 (survival of motor neuron 2, centromeric) genes that flank a divergent site at site c.840. Post-PCR high-resolution melt profiling assessed the amplification product, and we used a unique means of melt calibration to normalize profiles. Samples that we had previously characterized for the numbers of SMN1 and SMN2 copies established genotypes associated with particular profiles. The system was evaluated with approximately 1000 purified DNA samples, 100 self-created dried blood spots, and >1200 dried blood spots from newborn screening tests. RESULTS Homozygous deletion of SMN1 exon 7 produced a distinctive melt profile that identified SMA patients. Samples with different numbers of SMN1 and SMN2 copies were resolved by their profiles. All samples with homozygous deletions were unambiguously recognized, and no normal sample was misidentified as a positive. CONCLUSIONS This assay has characteristics suitable for population-based screening. A reliable screening test will facilitate the identification of an SMA-affected cohort to receive early intervention to maximize the benefit from treatment. A prospective screening trial will allow the efficacy of treatment options to be assessed, which may justify the inclusion of SMA as a target for population screening.

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The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein

Molecular Biology of the Cell ◽

10.1091/mbc.e13-01-0042 ◽

2013 ◽

Vol 24 (12) ◽

pp. 1863-1871 ◽

Cited By ~ 32

Author(s):

Deborah Y. Kwon ◽

Maria Dimitriadi ◽

Barbara Terzic ◽

Casey Cable ◽

Anne C. Hart ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Ubiquitin Ligase ◽

Cultured Cells ◽

Muscular Atrophy ◽

E3 Ubiquitin Ligase ◽

Proteasome Inhibition ◽

Protein Levels ◽

Smn Protein ◽

Survival Of Motor Neuron

Spinal muscular atrophy is an inherited motor neuron disease that results from a deficiency of the survival of motor neuron (SMN) protein. SMN is ubiquitinated and degraded through the ubiquitin proteasome system (UPS). We have previously shown that proteasome inhibition increases SMN protein levels, improves motor function, and reduces spinal cord, muscle, and neuromuscular junction pathology of spinal muscular atrophy (SMA) mice. Specific targets in the UPS may be more efficacious and less toxic. In this study, we show that the E3 ubiquitin ligase, mind bomb 1 (Mib1), interacts with and ubiquitinates SMN and facilitates its degradation. Knocking down Mib1 levels increases SMN protein levels in cultured cells. Also, knocking down the Mib1 orthologue improves neuromuscular function in Caenorhabditis elegans deficient in SMN. These findings demonstrate that Mib1 ubiquitinates and catalyzes the degradation of SMN, and thus represents a novel therapeutic target for SMA.

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Spinal Muscular Atrophy

10.1093/med/9780199937837.003.0033 ◽

2017 ◽

Author(s):

Umrao R. Monani ◽

Darryl C. De Vivo

Keyword(s):

Infant Mortality ◽

Life Expectancy ◽

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Carrier Frequency ◽

Muscular Atrophy ◽

Good Treatment ◽

Motor Neuron Disorder ◽

Smn Protein ◽

Survival Of Motor Neuron

Spinal muscular atrophy (SMA) is a common, inherited, pediatric motor neuron disorder caused by insufficient SMN protein. As of yet, there is no good treatment for the disease. SMA has an incidence of ~1 in 10,000 newborns carrier frequency of 1 in 50, making it the most common inherited cause of infant mortality. Patients with severe SMA, or Werdnig-Hoffman disease, typically manifest weakness during the first 6 months of life. Such patients are so debilitated that they never sit independently, frequently succumbing to the disease before age 2 years. A much milder form of SMA, Kugelberg-Welander disease, with onset after 18 months of age, often during childhood and characterized by prolonged ambulation and a normal life expectancy, was described in 1956. In 1995 mutations in a novel gene, Survival of Motor Neuron 1 (SMN1), were determined to be the specific cause of SMA.

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Genetic modifiers ameliorate endocytic and neuromuscular defects in a model of spinal muscular atrophy

BMC Biology ◽

10.1186/s12915-020-00845-w ◽

2020 ◽

Vol 18 (1) ◽

Cited By ~ 1

Author(s):

Melissa B. Walsh ◽

Eva Janzen ◽

Emily Wingrove ◽

Seyyedmohsen Hosseinibarkooie ◽

Natalia Rodriguez Muela ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Muscular Atrophy ◽

Protein Complexes ◽

Genetic Modifiers ◽

Functional Connection ◽

C Elegans ◽

Hnrnp F ◽

Smn Protein ◽

Survival Of Motor Neuron

Abstract Background Understanding the genetic modifiers of neurodegenerative diseases can provide insight into the mechanisms underlying these disorders. Here, we examine the relationship between the motor neuron disease spinal muscular atrophy (SMA), which is caused by reduced levels of the survival of motor neuron (SMN) protein, and the actin-bundling protein Plastin 3 (PLS3). Increased PLS3 levels suppress symptoms in a subset of SMA patients and ameliorate defects in SMA disease models, but the functional connection between PLS3 and SMN is poorly understood. Results We provide immunohistochemical and biochemical evidence for large protein complexes localized in vertebrate motor neuron processes that contain PLS3, SMN, and members of the hnRNP F/H family of proteins. Using a Caenorhabditis elegans (C. elegans) SMA model, we determine that overexpression of PLS3 or loss of the C. elegans hnRNP F/H ortholog SYM-2 enhances endocytic function and ameliorates neuromuscular defects caused by decreased SMN-1 levels. Furthermore, either increasing PLS3 or decreasing SYM-2 levels suppresses defects in a C. elegans ALS model. Conclusions We propose that hnRNP F/H act in the same protein complex as PLS3 and SMN and that the function of this complex is critical for endocytic pathways, suggesting that hnRNP F/H proteins could be potential targets for therapy development.

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