scholarly journals A screen for regulators of survival of motor neuron protein levels

2011 ◽  
Vol 7 (8) ◽  
pp. 544-552 ◽  
Author(s):  
Nina R Makhortova ◽  
Monica Hayhurst ◽  
Antonio Cerqueira ◽  
Amy D Sinor-Anderson ◽  
Wen-Ning Zhao ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Protein Levels ◽  
Motor Neuron Protein ◽  
Survival Of Motor Neuron

scholarly journals Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron

2018 ◽  
Vol 29 (2) ◽  
pp. 96-110 ◽  
Author(s):  
Kelsey M. Gray ◽  
Kevin A. Kaifer ◽  
David Baillat ◽  
Ying Wen ◽  
Thomas R. Bonacci ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Protein Isoforms ◽  
Survival Motor Neuron Protein ◽  
Protein Levels ◽  
Motor Neuron Protein ◽  
Smn Protein ◽  
Oligomerization Domain

SMN protein levels inversely correlate with the severity of spinal muscular atrophy. The SCFSlmbE3 ligase complex interacts with a degron embedded within the C-terminal self-oligomerization domain of SMN. The findings elucidate a model whereby accessibility of the SMN degron is regulated by self-multimerization.

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.

A role for the survival of motor neuron protein in mRNP assembly and transport

2016 ◽  
Vol 39 ◽  
pp. 53-61 ◽  
Author(s):  
Paul G Donlin-Asp ◽  
Gary J Bassell ◽  
Wilfried Rossoll
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Protein ◽  
Survival Of Motor Neuron

scholarly journals Survival of motor neuron protein downregulates miR-9 expression in patients with spinal muscular atrophy

2014 ◽  
Vol 30 (5) ◽  
pp. 229-234 ◽  
Author(s):  
Li-Ting Wang ◽  
Shyh-Shin Chiou ◽  
Yu-Mei Liao ◽  
Yuh-Jyh Jong ◽  
Shih-Hsien Hsu
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Motor Neuron Protein ◽  
Survival Of Motor Neuron

scholarly journals Whole blood survival motor neuron protein levels correlate with severity of denervation in spinal muscular atrophy

2020 ◽  
Vol 62 (3) ◽  
pp. 351-357 ◽  
Author(s):  
Christiano R. R. Alves ◽  
Ren Zhang ◽  
Alec J. Johnstone ◽  
Reid Garner ◽  
Eric J. Eichelberger ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Whole Blood ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Survival Motor Neuron Protein ◽  
Protein Levels ◽  
Motor Neuron Protein

Nusinersen in the treatment of 5q spinal muscular atrophy (Sponsor: Biogen GmbH, München)

2020 ◽  
Vol 12 (02) ◽  
pp. 1-24
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Antisense Oligonucleotide ◽  
Muscle Function ◽  
Muscular Atrophy ◽  
Smn1 Gene ◽  
Motor Neuron Protein ◽  
Smn Protein ◽  
Survival Of Motor Neuron ◽  
Progressive Weakness

AbstractDue to a mutation in the SMN1 gene on chromosome 5, in 5q-SMA there is a deficiency in the survival of motor neuron protein (SMA) which is essential for motor neurons. This leads to a degeneration of the 2nd motor neuron and progressive weakness and atrophy of the affected muscles. The targeted splicing modulator nusinersen (Spinraza®), an antisense oligonucleotide that binds to the SMN2-RNA, leads to increased production of functional SMN protein. This stabilizes the disease and improves muscle function.

scholarly journals CIM Journal Club: Gene therapy for spinal muscular atrophy Comment on Mendell et al. N Engl J Med 2017;377:1713-22.

2018 ◽  
pp. E31-E33 ◽  
Author(s):  
Raphael Schneider
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Viral Vector ◽  
Muscular Atrophy ◽  
Journal Club ◽  
Dna Encoding ◽  
Motor Neuron Diseases ◽  
Motor Neuron Protein ◽  
Survival Of Motor Neuron

In their landmark paper, Mendell et al. show that infants with spinal muscular atrophy (SMA) reached important motor milestones and survived longer when treated with AVXS-101 (AveXis), a viral vector containing DNA encoding the survival of motor neuron protein (SMN). Patients not only crawled, stood and walked independently, but learned to speak. These results are very encouraging for patients with SMA and offer hope for pediatric and adult patients with other types of motor neuron diseases.

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