scholarly journals Reduced Survival of Motor Neuron (SMN) Protein in Motor Neuronal Progenitors Functions Cell Autonomously to Cause Spinal Muscular Atrophy in Model Mice Expressing the Human Centromeric (SMN2) Gene

2010 ◽  
Vol 30 (36) ◽  
pp. 12005-12019 ◽  
Author(s):  
G.-H. Park ◽  
Y. Maeno-Hikichi ◽  
T. Awano ◽  
L. T. Landmesser ◽  
U. R. Monani
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Neuronal Progenitors ◽  
Smn2 Gene ◽  
Smn Protein ◽  
Survival Of Motor Neuron

scholarly journals Identification of Novel Compounds That Increase SMN Protein Levels Using an Improved SMN2 Reporter Cell Assay

2012 ◽  
Vol 17 (4) ◽  
pp. 481-495 ◽  
Author(s):  
Jonathan J. Cherry ◽  
Matthew C. Evans ◽  
Jake Ni ◽  
Gregory D. Cuny ◽  
Marcie A. Glicksman ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Neurodegenerative Disorder ◽  
Muscular Atrophy ◽  
Full Length ◽  
Reporter Cell ◽  
Protein Levels ◽  
Smn2 Gene ◽  
Smn Protein ◽  
Neuron Function ◽  
Survival Of Motor Neuron

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.

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.

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 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.

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

2018 ◽  
Vol 61 (15) ◽  
pp. 6501-6517 ◽  
Author(s):  
Hasane Ratni ◽  
Martin Ebeling ◽  
John Baird ◽  
Stefanie Bendels ◽  
Johan Bylund ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Gene Splicing ◽  
Smn2 Gene ◽  
Selective Survival ◽  
Survival Of Motor Neuron

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
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