scholarly journals In Vivo Translatome Profiling in Spinal Muscular Atrophy Reveals a Role for SMN Protein in Ribosome Biology

Cell Reports ◽  
2017 ◽  
Vol 21 (4) ◽  
pp. 953-965 ◽  
Author(s):  
Paola Bernabò ◽  
Toma Tebaldi ◽  
Ewout J.N. Groen ◽  
Fiona M. Lane ◽  
Elena Perenthaler ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Smn Protein

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.

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.

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.

In Vitro and In Vivo Models of Spinal Muscular Atrophy

2017 ◽  
Author(s):  
W. David Arnold ◽  
Arthur H. M. Burghes
Keyword(s):  
Tissue Culture ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
In Vivo Models ◽  
Culture Cells ◽  
Tissue Culture Cells ◽  
Smn Protein

Spinal muscular Atrophy (SMA) is caused by reduced levels of the SMN protein. In humans this is caused by loss of SMN1 and retention of SMN2. The challenge in modelling SMA, in either tissue culture cells or animals, is first to obtain the desired SMN levels equivalent to what is observed in SMA. Various models of SMA in tissue culture cells, invertebrates, and mammals have been created have been developed. The targets of SMN reduction that are most relevant for the pathogenesis of SMA and how the phenotype of SMA can be modified independent of SMN levels are two important questions that remain unanswered. Here the current in vitro and in vivo models of SMA are summarized.

SMN mRNA and protein levels in peripheral blood

Neurology ◽  
2006 ◽  
Vol 66 (7) ◽  
pp. 1067-1073 ◽  
Author(s):  
C. J. Sumner ◽  
S. J. Kolb ◽  
G. G. Harmison ◽  
N. O. Jeffries ◽  
K. Schadt ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Peripheral Blood ◽  
Muscular Atrophy ◽  
Gene Copy ◽  
Blood Levels ◽  
Type I ◽  
Protein Levels ◽  
Smn Protein

Background: Clinical trials of drugs that increase SMN protein levels in vitro are currently under way in patients with spinal muscular atrophy.Objective: To develop and validate measures of SMN mRNA and protein in peripheral blood and to establish baseline SMN levels in a cohort of controls, carriers, and patients of known genotype, which could be used to follow response to treatment.Methods: SMN1 and SMN2 gene copy numbers were determined in blood samples collected from 86 subjects. Quantitative reverse transcription PCR was used to measure blood levels of SMN mRNA with and without exon 7. A cell immunoassay was used to measure blood levels of SMN protein.Results: Blood levels of SMN mRNA and protein were measured with high reliability. There was little variation in SMN levels in individual subjects over a 5-week period. Levels of exon 7-containing SMN mRNA and SMN protein correlated with SMN1 and SMN2 gene copy number. With the exception of type I SMA, there was no correlation between SMN levels and disease severity.Conclusion: SMN mRNA and protein levels can be reliably measured in the peripheral blood and used during clinical trials in spinal muscular atrophy, but these levels do not necessarily predict disease severity.

scholarly journals Calpain Inhibition Increases SMN Protein in Spinal Cord Motoneurons and Ameliorates the Spinal Muscular Atrophy Phenotype in Mice

2018 ◽  
Vol 56 (6) ◽  
pp. 4414-4427 ◽  
Author(s):  
Sandra de la Fuente ◽  
Alba Sansa ◽  
Ambika Periyakaruppiah ◽  
Ana Garcera ◽  
Rosa M. Soler
Keyword(s):  
Spinal Cord ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Smn Protein ◽  
Calpain Inhibition

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 Temporal and tissue-specific variability of SMN protein levels in mouse models of spinal muscular atrophy

2018 ◽  
Vol 27 (16) ◽  
pp. 2851-2862 ◽  
Author(s):  
Ewout J N Groen ◽  
Elena Perenthaler ◽  
Natalie L Courtney ◽  
Crispin Y Jordan ◽  
Hannah K Shorrock ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Mouse Models ◽  
Muscular Atrophy ◽  
Tissue Specific ◽  
Protein Levels ◽  
Smn Protein
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