What Genetics Has Told Us and How It Can Inform Future Experiments for Spinal Muscular Atrophy, a Perspective

Proximal spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by motor neuron loss and subsequent atrophy of skeletal muscle. SMA is caused by deficiency of the essential survival motor neuron (SMN) protein, canonically responsible for the assembly of the spliceosomal small nuclear ribonucleoproteins (snRNPs). Therapeutics aimed at increasing SMN protein levels are efficacious in treating SMA. However, it remains unknown how deficiency of SMN results in motor neuron loss, resulting in many reported cellular functions of SMN and pathways affected in SMA. Herein is a perspective detailing what genetics and biochemistry have told us about SMA and SMN, from identifying the SMA determinant region of the genome, to the development of therapeutics. Furthermore, we will discuss how genetics and biochemistry have been used to understand SMN function and how we can determine which of these are critical to SMA moving forward.

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

International Journal of Scientific Research in Computer Science Engineering and Information Technology ◽

10.32628/cseit195142 ◽

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.

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The influence of storage parameters on measurement of survival motor neuron (SMN) protein levels: Implications for pre-clinical studies and clinical trials for spinal muscular atrophy

Neuromuscular Disorders ◽

10.1016/j.nmd.2014.05.013 ◽

2014 ◽

Vol 24 (11) ◽

pp. 973-977 ◽

Cited By ~ 4

Author(s):

Gillian Hunter ◽

Sarah L. Roche ◽

Eilidh Somers ◽

Heidi R. Fuller ◽

Thomas H. Gillingwater

Keyword(s):

Clinical Trials ◽

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Clinical Studies ◽

Muscular Atrophy ◽

Survival Motor Neuron ◽

Protein Levels ◽

Smn Protein

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

Molecular Biology of the Cell ◽

10.1091/mbc.e17-11-0627 ◽

2018 ◽

Vol 29 (2) ◽

pp. 96-110 ◽

Cited By ~ 15

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.

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Modeling spinal muscular atrophy in Drosophila links Smn to FGF signaling

The Journal of Cell Biology ◽

10.1083/jcb.201004016 ◽

2011 ◽

Vol 192 (3) ◽

pp. 481-495 ◽

Cited By ~ 32

Author(s):

Anindya Sen ◽

Takakazu Yokokura ◽

Mark W. Kankel ◽

Douglas N. Dimlich ◽

Jan Manent ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Neurodegenerative Disorder ◽

Muscular Atrophy ◽

Survival Motor Neuron ◽

Fgf Signaling ◽

Human Pathology ◽

Smn Gene ◽

Motor Neuron Loss ◽

Signaling Components

Spinal muscular atrophy (SMA), a devastating neurodegenerative disorder characterized by motor neuron loss and muscle atrophy, has been linked to mutations in the Survival Motor Neuron (SMN) gene. Based on an SMA model we developed in Drosophila, which displays features that are analogous to the human pathology and vertebrate SMA models, we functionally linked the fibroblast growth factor (FGF) signaling pathway to the Drosophila homologue of SMN, Smn. Here, we characterize this relationship and demonstrate that Smn activity regulates the expression of FGF signaling components and thus FGF signaling. Furthermore, we show that alterations in FGF signaling activity are able to modify the neuromuscular junction defects caused by loss of Smn function and that muscle-specific activation of FGF is sufficient to rescue Smn-associated abnormalities.

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

Acta Neuropathologica Communications ◽

10.1186/s40478-020-01101-6 ◽

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.

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Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

Journal of Experimental Neuroscience ◽

10.4137/jen.s33122 ◽

2016 ◽

Vol 10 ◽

pp. JEN.S33122 ◽

Cited By ~ 36

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.

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

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057111431605 ◽

2012 ◽

Vol 17 (4) ◽

pp. 481-495 ◽

Cited By ~ 18

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.

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Sensory Neurons Do Not Induce Motor Neuron Loss in a Human Stem Cell Model of Spinal Muscular Atrophy

PLoS ONE ◽

10.1371/journal.pone.0103112 ◽

2014 ◽

Vol 9 (7) ◽

pp. e103112 ◽

Cited By ~ 9

Author(s):

Andrew J. Schwab ◽

Allison D. Ebert

Keyword(s):

Stem Cell ◽

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Sensory Neurons ◽

Muscular Atrophy ◽

Cell Model ◽

Human Stem Cell ◽

Neuron Loss ◽

Stem Cell Model ◽

Motor Neuron Loss

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The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein

Molecular Biology of the Cell ◽

10.1091/mbc.e13-01-0042 ◽

2013 ◽

Vol 24 (12) ◽

pp. 1863-1871 ◽

Cited By ~ 32

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.

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