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 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 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 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 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.

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 Short-duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy

2020 ◽  
Vol 4 (1) ◽  
pp. e202000889
Author(s):  
Anne Rietz ◽  
Kevin J Hodgetts ◽  
Hrvoje Lusic ◽  
Kevin M Quist ◽  
Erkan Y Osman ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Antisense Oligonucleotides ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Potential Drug ◽  
Transgenic Mouse Models ◽  
Fda Approval ◽  
Smn Protein

Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality. SMA results from insufficient survival motor neuron (SMN) protein due to alternative splicing. Antisense oligonucleotides, gene therapy and splicing modifiers recently received FDA approval. Although severe SMA transgenic mouse models have been beneficial for testing therapeutic efficacy, models mimicking milder cases that manifest post-infancy have proven challenging to develop. We established a titratable model of mild and moderate SMA using the splicing compound NVS-SM2. Administration for 30 d prevented development of the SMA phenotype in severe SMA mice, which typically show rapid weakness and succumb by postnatal day 11. Furthermore, administration at day eight resulted in phenotypic recovery. Remarkably, acute dosing limited to the first 3 d of life significantly enhanced survival in two severe SMA mice models, easing the burden on neonates and demonstrating the compound as suitable for evaluation of follow-on therapies without potential drug–drug interactions. This pharmacologically tunable SMA model represents a useful tool to investigate cellular and molecular pathogenesis at different stages of disease.

scholarly journals Fluorescence Correlation Spectroscopy Reveals Survival Motor Neuron Oligomerization but No Active Transport in Motor Axons of a Zebrafish Model for Spinal Muscular Atrophy

2021 ◽  
Vol 9 ◽  
Author(s):  
Angela Koh ◽  
Menachem Viktor Sarusie ◽  
Jürgen Ohmer ◽  
Utz Fischer ◽  
Christoph Winkler ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Active Transport ◽  
Fluorescence Correlation Spectroscopy ◽  
Muscular Atrophy ◽  
Correlation Spectroscopy ◽  
Survival Motor Neuron ◽  
Transgenic Zebrafish ◽  
Fluorescence Correlation

Spinal Muscular Atrophy (SMA) is a progressive neurodegenerative disease affecting lower motor neurons that is caused by a deficiency in ubiquitously expressed Survival Motor Neuron (SMN) protein. Two mutually exclusive hypotheses have been discussed to explain increased motor neuron vulnerability in SMA. Reduced SMN levels have been proposed to lead to defective snRNP assembly and aberrant splicing of transcripts that are essential for motor neuron maintenance. An alternative hypothesis proposes a motor neuron-specific function for SMN in axonal transport of mRNAs and/or RNPs. To address these possibilities, we used a novel in vivo approach with fluorescence correlation spectroscopy (FCS) in transgenic zebrafish embryos to assess the subcellular dynamics of Smn in motor neuron cell bodies and axons. Using fluorescently tagged Smn we show that it exists as two freely diffusing components, a monomeric, and a complex-bound, likely oligomeric, component. This oligomer hypothesis was supported by the disappearance of the complex-bound form for a truncated Smn variant that is deficient in oligomerization and a change in its dynamics under endogenous Smn deficient conditions. Surprisingly, our FCS measurements did not provide any evidence for an active transport of Smn in axons. Instead, our in vivo observations are consistent with previous findings that SMN acts as a chaperone for the assembly of snRNP and mRNP complexes.

Novel protective modifiers in mouse models of spinal muscular atrophy

2018 ◽  
Author(s):  
◽  
Kevin Andrew Cody Kaifer
Keyword(s):  
Spinal Muscular Atrophy ◽  
Mouse Models ◽  
Muscular Atrophy ◽  
Experimental System ◽  
Homozygous Deletion ◽  
Alpha Synuclein ◽  
Survival Motor Neuron ◽  
Virus Serotype ◽  
Smn Protein

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by the homozygous deletion or mutation in the survival motor neuron-1 (SMN1) gene resulting in extremely low levels of the SMN protein. Without treatment, the majority of SMA cases progress rapidly and lead to mortality by age 2. SMA is uniquely positioned for therapy, however, as a nearly identical gene called SMN2 can be modulated to express the functional SMN protein. A recently approved, highly efficacious therapy called Spinraza adopts this strategy and has brought promise to the SMA patient community. Despite this breakthrough, it is widely hypothesized that a long-term strategy will require a combinatorial approach to address the complexity of this disease, and additional therapeutic strategies need to be established. Towards this aim, the past decade of research has led to the elucidation of key molecular events that contribute to the pathology of SMA as well as several factors that modulate disease severity. Referred to as protective modifiers, these factors represent potential targets for combinatorial therapy. In this work we establish a strategy to identify and characterize novel protective modifiers in mouse models of SMA. Our approach utilizes adenoassociated virus serotype 9 (AAV9) to express putative modifiers in mouse models, effectively allowing us to determine their effects in vivo. Using our experimental system, we confirm that a previously controversial modifier, Plastin-3, reduces severity in mouse models of SMA. We also identify miR-23a, DOK7, and [alpha]-synuclein as novel protective modifiers of SMA. These insights implicate microRNA dysregulation, neuromuscular junction organization, and synaptic transmission as disease modifying pathways that contain potential therapeutic candidates for the treatment of SMA.

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