scholarly journals Examine the role of minor splicing pathway in spinal muscular atrophy

2014 ◽  
Author(s):  
◽  
Pei-Fen Yen
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Autosomal Recessive Disorder ◽  
Potential Effect ◽  
Survival Motor Neuron ◽  
Disease Phenotypes ◽  
Peak Weight ◽  
Central Synapses

Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder mainly caused by deletions or mutations of one gene, Survival Motor Neuron (SMN). SMN is crucial in splicing processes for proper gene expression. Previous studies showed a significant decrease in the levels of minor splicing (U12 intron) snRNPs in SMA mice and a restoration of a U12 intron-containing gene partially rescued disease phenotypes in SMA animal models. Here we utilized viral delivery system to investigate the potential effect of increasing minor splicing snRNAs on SMN deficiency. We introduced minor splicing snRNAs, human U11 and U12, or human U11, U12 with U4atac to the well-characterized SMA mice. Our treatment prolonged survival and increased percent peak weight gain. The motor function was improved however NMJ pathology was largely uncorrected. Nonetheless, the increment of minor splicing snRNAs maintained the number of central synapses on motor neurons. Furthermore, no changes in SMN expression after the treatment indicated that increasing minor splicing snRNAs partially benefits disease phenotypes independent to SMN expression in SMA mice. Furthermore, defects in U12-intron splicing events were partially corrected for U12 intron-containing SMN target gene, Stasimon, reiterating the improvement of minor splicing in SMA mice. Taken together, our results showed the restoration of minor splicing snRNAs partially ameliorates SMN deficiency caused phenotypes, indicating that U12-dependent minor splicing event is responsible for the disease progress of SMA.

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 Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: implications for a neuromuscular disorder, spinal muscular atrophy

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Wiebke A. Rehorst ◽  
Maximilian P. Thelen ◽  
Hendrik Nolte ◽  
Clara Türk ◽  
Sebahattin Cirak ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neuromuscular Disorder ◽  
Survival Motor Neuron ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Metabolic Labeling

Abstract Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder, which causes dysfunction/loss of lower motor neurons and muscle weakness as well as atrophy. While SMA is primarily considered as a motor neuron disease, recent data suggests that survival motor neuron (SMN) deficiency in muscle causes intrinsic defects. We systematically profiled secreted proteins from control and SMN deficient muscle cells with two combined metabolic labeling methods and mass spectrometry. From the screening, we found lower levels of C1q/TNF-related protein 3 (CTRP3) in the SMA muscle secretome and confirmed that CTRP3 levels are indeed reduced in muscle tissues and serum of an SMA mouse model. We identified that CTRP3 regulates neuronal protein synthesis including SMN via mTOR pathway. Furthermore, CTRP3 enhances axonal outgrowth and protein synthesis rate, which are well-known impaired processes in SMA motor neurons. Our data revealed a new molecular mechanism by which muscles regulate the physiology of motor neurons via secreted molecules. Dysregulation of this mechanism contributes to the pathophysiology of SMA.

scholarly journals Cellular bases of the RNA metabolism dysfunction in motor neurons of a murine model of spinal muscular atrophy: Role of Cajal bodies and the nucleolus

2017 ◽  
Vol 108 ◽  
pp. 83-99 ◽  
Author(s):  
Olga Tapia ◽  
Josep Oriol Narcís ◽  
Javier Riancho ◽  
Olga Tarabal ◽  
Lídia Piedrafita ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Murine Model ◽  
Muscular Atrophy ◽  
Rna Metabolism ◽  
Cajal Bodies

scholarly journals Circulating microRNAs as potential biomarkers and therapeutic targets in spinal muscular atrophy

2020 ◽  
Vol 13 ◽  
pp. 175628642097995
Author(s):  
Tai-Heng Chen
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Muscular Atrophy ◽  
Therapeutic Targets ◽  
Homozygous Deletion ◽  
Survival Motor Neuron ◽  
Novel Mirna ◽  
Potential Applications ◽  
Smn Protein

Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterized by the selective loss of particular groups of motor neurons (MNs) in the anterior horn of the spinal cord with progressive muscle wasting. SMA is caused by a deficiency of the survival motor neuron (SMN) protein due to a homozygous deletion or mutation of the SMN1 gene. However, the molecular mechanisms whereby the SMN complex regulates MN functions are not fully elucidated. Emerging studies on SMA pathogenesis have turned the attention of researchers to RNA metabolism, given that increasingly identified SMN-associated modifiers are involved in both coding and non-coding RNA (ncRNA) processing. Among various ncRNAs, microRNAs (miRNAs) are the most studied in terms of regulation of posttranscriptional gene expression. Recently, the discovery that miRNAs are critical to MN function and survival led to the study of dysregulated miRNAs in SMA pathogenesis. Circulating miRNAs have drawn attention as a readily available biomarker due to their property of being clinically detectable in numerous human biofluids through non-invasive approaches. As there are recent promising findings from novel miRNA-based medicines, this article presents an extensive review of the most up-to-date studies connecting specific miRNAs to SMA pathogenesis and the potential applications of miRNAs as biomarkers and therapeutic targets for SMA.

scholarly journals Key role of SMN/SYNCRIP and RNA-Motif 7 in spinal muscular atrophy: RNA-Seq and motif analysis of human motor neurons

Brain ◽  
2019 ◽  
Vol 142 (2) ◽  
pp. 276-294 ◽  
Author(s):  
Federica Rizzo ◽  
Monica Nizzardo ◽  
Shikha Vashisht ◽  
Erika Molteni ◽  
Valentina Melzi ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Rna Seq ◽  
Motif Analysis ◽  
Human Motor ◽  
Rna Motif

scholarly journals Combining multi-omics and drug perturbation profiles to identify novel treatments that improve disease phenotypes in spinal muscular atrophy

2019 ◽  
Author(s):  
Katharina E. Meijboom ◽  
Viola Volpato ◽  
Jimena Monzón-Sandoval ◽  
Joseph M. Hoolachan ◽  
Suzan M. Hammond ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Neuromuscular Disorder ◽  
Survival Motor Neuron ◽  
Muscle Pathology ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Disease Phenotypes ◽  
Parallel Data ◽  
Smn Protein

ABSTRACTSpinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify novel treatments to alleviate muscle pathology combining transcriptomics, proteomics and perturbational datasets. This revealed potential drug candidates for repurposing in SMA. One of the lead candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including SMN expression and lifespan. Our work highlights the potential of multiple, parallel data driven approaches for development of novel treatments for use in combination with SMN restoration therapies.

scholarly journals Prion-like Conformational Editing of SMN2 Proteins Rescues Spinal Muscular Atrophy

2021 ◽  
Author(s):  
I-Fan Wang ◽  
Chen-Hung Ting ◽  
Li-Kai Tsai ◽  
Hsiang-Yu Chang ◽  
Hsing-Jung Lai ◽  
...  
Keyword(s):  
Phase Separation ◽  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Drug Candidate ◽  
Missense Mutations ◽  
Root Cause ◽  
Progressive Muscle Weakness ◽  
Effective Phase

Abstract Spinal muscular atrophy (SMA) causes the loss of motor neurons and progressive muscle weakness. In 95% of patients with SMA, both alleles of the survival motor neuron 1 (SMN1­) gene are deleted or the gene contains missense mutations. A nearly identical copy of SMN1, SMN2, is normally expressed but is unable to compensate for the loss of SMN1 due to the deletion of exon 7. Here, we demonstrated that conformational editing of the SMN2 protein triggers effective phase separation of SMN2 proteins and rescues SMA. We found that SMN1 contains a prion-like LC domain at exons 6-7, which drives liquid-liquid phase separation (LLPS) and further discovered an LLPS activator of gems, baicalein. Using baicalein, we reinvented SMN2 proteins into a competent prion-like conformation to restore the prion-like functions of SMN1 and effectively rescue SMA mice. Our study suggests that the impaired prion-like activity of SMN1 is the root cause of SMA and provides a drug candidate for SMA and phase separation-deficient diseases.

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.

Therapeutic targets for spinal muscular atrophy : Inhibiting the inhibitors

2014 ◽  
Author(s):  
◽  
Erkan Y. Osman
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Complex Disease ◽  
Muscular Atrophy ◽  
Autosomal Recessive Disorder ◽  
Therapeutic Strategies ◽  
Cellular Level ◽  
Survival Motor Neuron ◽  
Clinical Consequence ◽  
University Of Missouri

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is a leading genetic cause of infantile death. SMA is the most common inherited motor neuron disease and occurs in approximately 1: 6,000 live births. The gene responsible for SMA is called survival motor neuron-1 (SMN1). A human-specific copy gene is present on the same region of chromosome 5q called SMN2. SMN2 is nearly identical to SMN1; however, mutations in SMN2 have no clinical consequence if SMN1 is retained. The reason why SMN2 cannot prevent disease development in the absence of SMN1 is that the majority of SMN2-derived transcripts are alternatively spliced, resulting in a truncated and unstable protein. The presence of SMN2 in all SMA patients is fundamental to the biology of the disease; however, from a translational perspective, targeting SMN2 may prove to be the most important therapeutic opportunity for all patients. The presence of SMN2 opens the door to a number of exciting therapeutic strategies, including anti-sense oligonucleotides (ASOs) that prevent the pathogenic SMN2 splicing event. Our efforts are focused on several repressor regions upstream and downstream of SMN2 exon 7. Importantly, when manipulating these repressor regions, hallmarks of the disease at the cellular level such as neuromuscular junction pathology in various SMA animal models are corrected. Currently, there are no approved SMA-specific compounds, and developing a broad array of therapeutic strategies to address this complex disease is essential. The development and design of highly-potent ASOs provide novel molecular targets for SMA therapeutics that can dramatically improve disease phenotype and extend patients' life span.

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