Spinal Muscular Atrophy

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.

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

2013 ◽  
Vol 24 (12) ◽  
pp. 1863-1871 ◽  
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.

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

BMC Biology ◽  
2020 ◽  
Vol 18 (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.

scholarly journals Decreased microRNA levels lead to deleterious increases in neuronal M2 muscarinic receptors in Spinal Muscular Atrophy models

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Patrick J O'Hern ◽  
Inês do Carmo G. Gonçalves ◽  
Johanna Brecht ◽  
Eduardo Javier López Soto ◽  
Jonah Simon ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Spinal Motor Neuron ◽  
C Elegans ◽  
M2 Muscarinic Receptor ◽  
Smn Protein ◽  
Survival Of Motor Neuron ◽  
Microrna Function ◽  
M2 Muscarinic Receptors

Spinal Muscular Atrophy (SMA) is caused by diminished Survival of Motor Neuron (SMN) protein, leading to neuromuscular junction (NMJ) dysfunction and spinal motor neuron (MN) loss. Here, we report that reduced SMN function impacts the action of a pertinent microRNA and its mRNA target in MNs. Loss of the C. elegans SMN ortholog, SMN-1, causes NMJ defects. We found that increased levels of the C. elegans Gemin3 ortholog, MEL-46, ameliorates these defects. Increased MEL-46 levels also restored perturbed microRNA (miR-2) function in smn-1(lf) animals. We determined that miR-2 regulates expression of the C. elegans M2 muscarinic receptor (m2R) ortholog, GAR-2. GAR-2 loss ameliorated smn-1(lf) and mel-46(lf) synaptic defects. In an SMA mouse model, m2R levels were increased and pharmacological inhibition of m2R rescued MN process defects. Collectively, these results suggest decreased SMN leads to defective microRNA function via MEL-46 misregulation, followed by increased m2R expression, and neuronal dysfunction in SMA.

Spinal Muscular Atrophy and the Antiapoptotic Role of Survival of Motor Neuron (SMN) Protein

2013 ◽  
Vol 47 (2) ◽  
pp. 821-832 ◽  
Author(s):  
Ryan S. Anderton ◽  
Bruno P. Meloni ◽  
Frank L. Mastaglia ◽  
Sherif Boulos
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Smn Protein ◽  
Survival Of Motor Neuron

scholarly journals Interaction between the small‐nuclear‐RNA cap hypermethylase and the spinal muscular atrophy protein, survival of motor neuron

EMBO Reports ◽  
2003 ◽  
Vol 4 (6) ◽  
pp. 616-622 ◽  
Author(s):  
John Mouaikel ◽  
Usha Narayanan ◽  
Céline Verheggen ◽  
A Gregory Matera ◽  
Edouard Bertrand ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Small Nuclear Rna ◽  
Nuclear Rna ◽  
Survival Of Motor Neuron

scholarly journals Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

2016 ◽  
Vol 10 ◽  
pp. JEN.S33122 ◽  
Author(s):  
Saif Ahmad ◽  
Kanchan Bhatia ◽  
Annapoorna Kannan ◽  
Laxman Gangwani
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Skeletal Muscle Atrophy ◽  
Spinal Motor Neurons ◽  
Low Levels ◽  
Smn Protein

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA.

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