scholarly journals Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding

2003 ◽  
Vol 162 (5) ◽  
pp. 919-932 ◽  
Author(s):  
Michelle L. McWhorter ◽  
Umrao R. Monani ◽  
Arthur H.M. Burghes ◽  
Christine E. Beattie
Keyword(s):  
Motor Neuron ◽  
Muscular Atrophy ◽  
Model Organism ◽  
Autosomal Recessive Disorder ◽  
Survival Motor Neuron ◽  
Motor Axon ◽  
Developmental Defects ◽  
Low Levels ◽  
Smn Protein

Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by a loss of α motoneurons in the spinal cord. SMA is caused by low levels of the ubiquitously expressed survival motor neuron (Smn) protein. As it is unclear how low levels of Smn specifically affect motoneurons, we have modeled SMA in zebrafish, a vertebrate model organism with well-characterized motoneuron development. Using antisense morpholinos to reduce Smn levels throughout the entire embryo, we found motor axon–specific pathfinding defects. Reduction of Smn in individual motoneurons revealed that smn is acting cell autonomously. These results show for the first time, in vivo, that Smn functions in motor axon development and suggest that these early developmental defects may lead to subsequent motoneuron loss.

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.

scholarly journals Utilizing gene therapy methods to probe the genetic requirements to prevent spinal muscular atrophy.

2016 ◽  
Author(s):  
◽  
Madeline R. Miller
Keyword(s):  
Neuromuscular Junction ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Downstream Effects ◽  
Smn Protein ◽  
Progressive Weakness

Spinal Muscular Atrophy is clinically recognized as a progressive weakness within the trunk and proximal limbs that will lead to breathing failure and death within infants. As a neurodegenerative genetic disease, SMA is caused by loss of motor neurons, which in turn is caused by low levels of the Survival Motor Neuron (SMN) protein. The mechanism by which a ubiquitously expressed protein such as SMN is able to cause the specific death of motor neurons is highly debated and of great interest. Work presented here focuses on understanding the biological requirements of SMN and its downstream effects on the neuromuscular junction. To this end we utilize viral based gene delivery as a powerful tool to assess the effects of genes of interest in vivo. Our findings contribute to the conversation regarding whether SMA is truly a "motor neuron" disease, suggesting that astrocytes play a meaningful role in staving off SMA. Further, we investigate the domains within SMN needed to maintain its function in a mammalian system. We take a novel and challenging approach to identify a minimal domain capable of maintaining function. Finally, we demonstrate the practical use of morophological analysis of the neuromuscular junction as a means to characterize SMA pathology.

scholarly journals SMN-primed ribosomes modulate the translation of transcripts related to Spinal Muscular Atrophy

2019 ◽  
Author(s):  
F Lauria ◽  
P Bernabò ◽  
T Tebaldi ◽  
EJN Groen ◽  
E Perenthaler ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Protein Loss ◽  
Molecular Control ◽  
Coding Sequence ◽  
Rare Codons ◽  
Smn Protein

AbstractThe contribution of ribosome heterogeneity and ribosome-associated factors to the molecular control of proteomes in health and disease remains enigmatic. We demonstrate that Survival Motor Neuron (SMN) protein, loss of which causes the neuromuscular disease spinal muscular atrophy (SMA), binds to ribosomes and that this interaction is tissue-dependent. SMN-primed ribosomes are positioned within the first five codons of a set of mRNAs which are enriched in IRES-like sequences in the 5’UTR and rare codons at the beginning of their coding sequence. Loss of SMN at early-stages of SMA induces translational defects in vivo, characterized by ribosome depletion in rare codons at the third and fifth position of the coding sequence. These positional defects cause ribosome depletion from mRNAs bound by SMN-primed ribosomes and translational impairment of proteins involved in motor neuron function and stability, including acetylcholinesterase. Thus, SMN plays a crucial role in the regulation of ribosome fluxes along mRNAs which encode proteins relevant to SMA pathogenesis.

scholarly journals SMN complex member Gemin3 self-interacts and has a functional relationship with ALS-linked proteins TDP-43, FUS and Sod1

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Rebecca Cacciottolo ◽  
Joanna Ciantar ◽  
Maia Lanfranco ◽  
Rebecca M. Borg ◽  
Neville Vassallo ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Muscular Atrophy ◽  
Model Organism ◽  
Survival Motor Neuron ◽  
Helicase Domain ◽  
Loss Of Function ◽  
Dead Box ◽  
Smn Complex ◽  
Wild Type Counterpart ◽  
Smn Protein

AbstractThe predominant motor neuron disease in infants and adults is spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), respectively. SMA is caused by insufficient levels of the Survival Motor Neuron (SMN) protein, which operates as part of the multiprotein SMN complex that includes the DEAD-box RNA helicase Gemin3/DDX20/DP103. C9orf72, SOD1, TDP-43 and FUS are ranked as the four major genes causing familial ALS. Accumulating evidence has revealed a surprising molecular overlap between SMA and ALS. Here, we ask the question of whether Drosophila can also be exploited to study shared pathogenic pathways. Focusing on motor behaviour, muscle mass and survival, we show that disruption of either TBPH/TDP-43 or Caz/FUS enhance defects associated with Gemin3 loss-of-function. Gemin3-associated neuromuscular junction overgrowth was however suppressed. Sod1 depletion had a modifying effect in late adulthood. We also show that Gemin3 self-interacts and Gem3ΔN, a helicase domain deletion mutant, retains the ability to interact with its wild-type counterpart. Importantly, mutant:wild-type dimers are favoured more than wild-type:wild-type dimers. In addition to reinforcing the link between SMA and ALS, further exploration of mechanistic overlaps is now possible in a genetically tractable model organism. Notably, Gemin3 can be elevated to a candidate for modifying motor neuron degeneration.

scholarly journals Mitochondrial defects in the respiratory complex I contribute to impaired translational initiation via ROS and energy homeostasis in SMA motor neurons

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Maximilian Paul Thelen ◽  
Brunhilde Wirth ◽  
Min Jeong Kye
Keyword(s):  
Protein Synthesis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Complex I ◽  
Energy Homeostasis ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Translational Initiation ◽  
Protein Levels ◽  
Smn Protein

AbstractSpinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of lower motor neurons, which leads to proximal muscle weakness and atrophy. SMA is caused by reduced survival motor neuron (SMN) protein levels due to biallelic deletions or mutations in the SMN1 gene. When SMN levels fall under a certain threshold, a plethora of cellular pathways are disturbed, including RNA processing, protein synthesis, metabolic defects, and mitochondrial function. Dysfunctional mitochondria can harm cells by decreased ATP production and increased oxidative stress due to elevated cellular levels of reactive oxygen species (ROS). Since neurons mainly produce energy via mitochondrial oxidative phosphorylation, restoring metabolic/oxidative homeostasis might rescue SMA pathology. Here, we report, based on proteome analysis, that SMA motor neurons show disturbed energy homeostasis due to dysfunction of mitochondrial complex I. This results in a lower basal ATP concentration and higher ROS production that causes an increase of protein carbonylation and impaired protein synthesis in SMA motor neurons. Counteracting these cellular impairments with pyruvate reduces elevated ROS levels, increases ATP and SMN protein levels in SMA motor neurons. Furthermore, we found that pyruvate-mediated SMN protein synthesis is mTOR-dependent. Most importantly, we showed that ROS regulates protein synthesis at the translational initiation step, which is impaired in SMA. As many neuropathies share pathological phenotypes such as dysfunctional mitochondria, excessive ROS, and impaired protein synthesis, our findings suggest new molecular interactions among these pathways. Additionally, counteracting these impairments by reducing ROS and increasing ATP might be beneficial for motor neuron survival in SMA patients.

scholarly journals AAV9-mediated delivery of miR-23a reduces disease severity in Smn2B/−SMA model mice

2019 ◽  
Vol 28 (19) ◽  
pp. 3199-3210 ◽  
Author(s):  
Kevin A Kaifer ◽  
Eric Villalón ◽  
Benjamin S O'Brien ◽  
Samantha L Sison ◽  
Caley E Smith ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Viral Vector ◽  
Muscular Atrophy ◽  
Induced Pluripotent Stem Cell ◽  
Survival Motor Neuron ◽  
Virus Serotype

Abstract Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in survival motor neuron 1 (SMN1). The molecular mechanisms underlying motor neuron degeneration in SMA remain elusive, as global cellular dysfunction obscures the identification and characterization of disease-relevant pathways and potential therapeutic targets. Recent reports have implicated microRNA (miRNA) dysregulation as a potential contributor to the pathological mechanism in SMA. To characterize miRNAs that are differentially regulated in SMA, we profiled miRNA levels in SMA induced pluripotent stem cell (iPSC)-derived motor neurons. From this array, miR-23a downregulation was identified selectively in SMA motor neurons, consistent with previous reports where miR-23a functioned in neuroprotective and muscle atrophy-antagonizing roles. Reintroduction of miR-23a expression in SMA patient iPSC-derived motor neurons protected against degeneration, suggesting a potential miR-23a-specific disease-modifying effect. To assess this activity in vivo, miR-23a was expressed using a self-complementary adeno-associated virus serotype 9 (scAAV9) viral vector in the Smn2B/− SMA mouse model. scAAV9-miR-23a significantly reduced the pathology in SMA mice, including increased motor neuron size, reduced neuromuscular junction pathology, increased muscle fiber area, and extended survival. These experiments demonstrate that miR-23a is a novel protective modifier of SMA, warranting further characterization of miRNA dysfunction in SMA.

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 Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA

2021 ◽  
Vol 13 (578) ◽  
pp. eabb6871
Author(s):  
Lingling Kong ◽  
David O. Valdivia ◽  
Christian M. Simon ◽  
Cera W. Hassinan ◽  
Nicolas Delestrée ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Radial Growth ◽  
Muscular Atrophy ◽  
Gene Replacement ◽  
Survival Motor Neuron ◽  
Motor Axon ◽  
Myelinated Axons ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Axon Development

Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination of severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence of developmentally immature motor neuron axons, many of which are actively degenerating. We identified similar features in a mouse model of severe SMA, in which impaired radial growth and Schwann cell ensheathment of motor axons began during embryogenesis and resulted in reduced acquisition of myelinated axons that impeded motor axon function neonatally. Axons that failed to ensheath degenerated rapidly postnatally, specifically releasing neurofilament light chain protein into the blood. Genetic restoration of survival motor neuron protein (SMN) expression in mouse motor neurons, but not in Schwann cells or muscle, improved SMA motor axon development and maintenance. Treatment with small-molecule SMN2 splice modifiers beginning immediately after birth in mice increased radial growth of the already myelinated axons, but in utero treatment was required to restore axonal growth and associated maturation, prevent subsequent neonatal axon degeneration, and enhance motor axon function. Together, these data reveal a cellular basis for the fulminant neonatal worsening of patients with infantile onset SMA and identify a temporal window for more effective treatment. These findings suggest that minimizing treatment delay is critical to achieve optimal therapeutic efficacy.

scholarly journals Spinal Muscular Atrophy Type B Awareness and Symptoms Prediction Using 3D Segmentation Process in MRI Images

2019 ◽  
pp. 312-318
Author(s):  
V. Manochithra ◽  
G. Sumithra
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Homozygous Deletion ◽  
Survival Motor Neuron ◽  
Molecular Testing ◽  
Prevention Measures ◽  
Neuron Loss ◽  
Motor Neuron Loss ◽  
Smn Protein

Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form of SMA, proximal or 5q SMA, and discuss the contemporary approach to diagnosis and treatment. Electromyography and muscle biopsy features of denervation were once the basis for diagnosis, but molecular testing for homozygous deletion or mutation of the SMN1 gene allows efficient and specific diagnosis. In combination with loss of SMN1, patients retain variable numbers of copies of a second similar gene, SMN2, which produce reduced levels of the survival motor neuron (SMN) protein that are insufficient for normal motor neuron function. Despite the fact that the understanding of how ubiquitous reduction of SMN protein leads to motor neuron loss remains incomplete, several promising therapeutics are now being tested in early phase clinical trials. This proposed model investigates the symptoms and scans readings from the initial MRI scan images of babies with mutation progress and SMN proteins formation benchmark values for this particular disorder SMA and further this segmented parameters are acquitted into the K-means clustering technique that predict the report with the disorder symptoms with MSE (mean square error) values that helps the babies in future to take prevention measures to overcome this problem.

Sign in / Sign up

Export Citation Format

Share Document