scholarly journals Therapy Development for Spinal Muscular Atrophy in SMN Independent Targets

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Li-Kai Tsai
Keyword(s):  
Spinal Muscular Atrophy ◽  
Effective Treatment ◽  
Motor Neurons ◽  
Kinase Inhibitor ◽  
Neurodegenerative Disorder ◽  
Muscular Atrophy ◽  
Rho Kinase ◽  
Premature Death ◽  
Survival Motor Neuron ◽  
Progressive Muscle Weakness

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder, leading to progressive muscle weakness, atrophy, and sometimes premature death. SMA is caused by mutation or deletion of thesurvival motor neuron-1 (SMN1) gene. An effective treatment does not presently exist. Since the severity of the SMA phenotype is inversely correlated with expression levels of SMN, theSMN-encoded protein, SMN is the most important therapeutic target for development of an effective treatment for SMA. In recent years, numerous SMN independent targets and therapeutic strategies have been demonstrated to have potential roles in SMA treatment. For example, some neurotrophic, antiapoptotic, and myotrophic factors are able to promote survival of motor neurons or improve muscle strength shown in SMA mouse models or clinical trials. Plastin-3, cpg15, and a Rho-kinase inhibitor regulate axonal dynamics and might reduce the influences of SMN depletion in disarrangement of neuromuscular junction. Stem cell transplantation in SMA model mice resulted in improvement of motor behaviors and extension of survival, likely from trophic support. Although most therapies are still under investigation, these nonclassical treatments might provide an adjunctive method for future SMA therapy.

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 The Relationship between Body Composition, Fatty Acid Metabolism and Diet in Spinal Muscular Atrophy

2021 ◽  
Vol 11 (2) ◽  
pp. 131
Author(s):  
Katherine S. Watson ◽  
Imane Boukhloufi ◽  
Melissa Bowerman ◽  
Simon H. Parson
Keyword(s):  
Body Composition ◽  
Fatty Acid ◽  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Muscular Atrophy ◽  
Fat Distribution ◽  
Survival Motor Neuron ◽  
Progressive Muscle Weakness

Spinal muscular atrophy (SMA) is an autosomal recessive condition that results in pathological deficiency of the survival motor neuron (SMN) protein. SMA most frequently presents itself within the first few months of life and is characterized by progressive muscle weakness. As a neuromuscular condition, it prominently affects spinal cord motor neurons and the skeletal muscle they innervate. However, over the past few decades, the SMA phenotype has expanded to include pathologies outside of the neuromuscular system. The current therapeutic SMA landscape is at a turning point, whereby a holistic multi-systemic approach to the understanding of disease pathophysiology is at the forefront of fundamental research and translational endeavours. In particular, there has recently been a renewed interest in body composition and metabolism in SMA patients, specifically that of fatty acids. Indeed, there is increasing evidence of aberrant fat distribution and fatty acid metabolism dysfunction in SMA patients and animal models. This review will explore fatty acid metabolic defects in SMA and discuss how dietary interventions could potentially be used to modulate and reduce the adverse health impacts of these perturbations in SMA patients.

scholarly journals AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of spinal muscular atrophy

2019 ◽  
Vol 28 (22) ◽  
pp. 3742-3754 ◽  
Author(s):  
E Villalón ◽  
R A Kline ◽  
C E Smith ◽  
Z C Lorson ◽  
E Y Osman ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Genetic Disorder ◽  
Premature Death ◽  
Survival Motor Neuron ◽  
Motor Neuron Diseases ◽  
Smn Protein

Abstract Spinal muscular atrophy (SMA) is a devastating infantile genetic disorder caused by the loss of survival motor neuron (SMN) protein that leads to premature death due to loss of motor neurons and muscle atrophy. The approval of an antisense oligonucleotide therapy for SMA was an important milestone in SMA research; however, effective next-generation therapeutics will likely require combinatorial SMN-dependent therapeutics and SMN-independent disease modifiers. A recent cross-disease transcriptomic analysis identified Stathmin-1 (STMN1), a tubulin-depolymerizing protein, as a potential disease modifier across different motor neuron diseases, including SMA. Here, we investigated whether viral-based delivery of STMN1 decreased disease severity in a well-characterized SMA mouse model. Intracerebroventricular delivery of scAAV9-STMN1 in SMA mice at P2 significantly increased survival and weight gain compared to untreated SMA mice without elevating Smn levels. scAAV9-STMN1 improved important hallmarks of disease, including motor function, NMJ pathology and motor neuron cell preservation. Furthermore, scAAV9-STMN1 treatment restored microtubule networks and tubulin expression without affecting tubulin stability. Our results show that scAAV9-STMN1 treatment improves SMA pathology possibly by increasing microtubule turnover leading to restored levels of stable microtubules. Overall, these data demonstrate that STMN1 can significantly reduce the SMA phenotype independent of restoring SMN protein and highlight the importance of developing SMN-independent therapeutics for the treatment 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 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 INNOVATIVE THERAPIES IN GENETIC DISEASES: SPINAL MUSCULAR ATROPHY

2021 ◽  
Vol 70 (2) ◽  
pp. 108-113
Author(s):  
Elena-Silvia Shelby ◽  
◽  
Andrada Mirea ◽  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Pediatric Population ◽  
Genetic Diseases ◽  
Short Review ◽  
Progressive Muscle Weakness ◽  
Innovative Therapies ◽  
Biallelic Mutations ◽  
Congenital Neuromuscular Disease

Spinal muscular atrophy is a congenital neuromuscular disease characterized by the deterioration of the motor neurons located mainly in the anterior horns of the spinal cord, leading to progressive muscle weakness and atrophy. Globally, SMA is, after cystic fibrosis, the second cause of death due to a a genetic disease in the pediatric population. Over 95% of the total cases of SMA are represented by 5q SMA, caused by biallelic mutations in the SMN1 gene (5q13.2), the rest of the SMA types being called, generically, non-5q SMA. Currently, a few genetic targeted therapies are available for 5q SMA, while other innovative therapies are still in clinical trials. Early diagnosis and treatment of 5q SMA have an essential role in preventing the onset and evolution of symptoms and can save the life of the patient and prevent debilitating sequelae. This article aims to briefly describe the cause and symptomatology of 5q SMA as well as to make a short review of the genetic therapies available for this disease.

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 Modeling spinal muscular atrophy in Drosophila links Smn to FGF signaling

2011 ◽  
Vol 192 (3) ◽  
pp. 481-495 ◽  
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.

scholarly journals Metabolic and Nutritional Issues Associated with Spinal Muscular Atrophy

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3842
Author(s):  
Yang-Jean Li ◽  
Tai-Heng Chen ◽  
Yan-Zhang Wu ◽  
Yung-Hao Tseng
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Nutritional Assessment ◽  
Muscular Atrophy ◽  
Nutritional Therapy ◽  
Survival Motor Neuron ◽  
Nutrition Support ◽  
Metabolic Abnormalities ◽  
Survival Motor Neuron Protein ◽  
The Impact

Spinal muscular atrophy (SMA), the main genetic cause of infant death, is a neurodegenerative disease characterized by the selective loss of motor neurons in the anterior horn of the spinal cord, accompanied by muscle wasting. Pathomechanically, SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from the loss of the SMN1 gene. However, emerging research extends the pathogenic effect of SMN deficiency beyond motor neurons. A variety of metabolic abnormalities, especially altered fatty acid metabolism and impaired glucose tolerance, has been described in isolated cases of SMA; therefore, the impact of SMN deficiency in metabolic abnormalities has been speculated. Although the life expectancy of these patients has increased due to novel disease-modifying therapies and standardization of care, understanding of the involvement of metabolism and nutrition in SMA is still limited. Optimal nutrition support and metabolic monitoring are essential for patients with SMA, and a comprehensive nutritional assessment can guide personalized nutritional therapy for this vulnerable population. It has recently been suggested that metabolomics studies before and after the onset of SMA in patients can provide valuable information about the direct or indirect effects of SMN deficiency on metabolic abnormalities. Furthermore, identifying and quantifying the specific metabolites in SMA patients may serve as an authentic biomarker or therapeutic target for SMA. Here, we review the main epidemiological and mechanistic findings that link metabolic changes to SMA and further discuss the principles of metabolomics as a novel approach to seek biomarkers and therapeutic insights in SMA.

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