scholarly journals Muscle microRNAs in the cerebrospinal fluid predict clinical response to nusinersen therapy in type II and type III spinal muscular atrophy patients

2021 ◽  
Author(s):  
Iddo Magen ◽  
Sharon Aharoni ◽  
Nancy Yacovzada ◽  
Itay Tokatly-Latzer ◽  
Christiano R R Alves ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Motor Neuron ◽  
Clinical Response ◽  
Motor Function ◽  
Messenger Rna ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Type Ii ◽  
Early Treatment Response ◽  
Noninvasive Biomarkers

Objective: The antisense oligonucleotide nusinersen (spinraza) regulates splicing of the survival motor neuron 2 (SMN2) messenger RNA to increase survival motor neuron (SMN) protein expression and has improved ventilator free survival and motor function outcomes in infantile onset forms of SMA, treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients. Methods: This is a multi-center longitudinal cohort study including a total of 34 type II or III SMA patients. We applied unbiased next-generation sequencing to identify cell-free microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers to predict response to nusinersen. Motor function, assessed by the Hammersmith Functional Motor Scale Expanded (HFMSE), was considered the primary clinical outcome. HFMSE was conducted at baseline and 6 months post initiation of nusinersen therapy. Patients with an improvement ≥ 3 points or no change or decline < 0 points in the HFMSE total score were considered to be responders or non-responders, respectively. Results: Lower baseline levels of two muscle microRNAs (miR-206 and miR-133), alone or in combination, were associated with the pre-determined clinical response to nusinersen after 6 months therapy. Moreover, miR-206 levels were inversely correlated with the HFMSE score. Conclusions: Lower miR-206 and miR-133 in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinsersen in later onset SMA patients and call to test the ability of miRNAs to predict more sustained long-term benefit.

scholarly journals Molecular Analysis of Survival Motor Neuron and Neuronal Apoptosis Inhibitory Protein Genes in Macedonian Spinal Muscular Atrophy Patients

2007 ◽  
Vol 10 (2) ◽  
pp. 55-60 ◽  
Author(s):  
S Kocheva ◽  
S Vlaski-Jekic ◽  
M Kuturec ◽  
G Efremov
Keyword(s):  
Motor Neuron ◽  
Neuronal Apoptosis ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Type I ◽  
Type Ii ◽  
Inhibitory Protein ◽  
Neuronal Apoptosis Inhibitory Protein ◽  
Smn Gene ◽  
Naip Gene

Molecular Analysis of Survival Motor Neuron and Neuronal Apoptosis Inhibitory Protein Genes in Macedonian Spinal Muscular Atrophy PatientsSpinal muscular atrophy (SMA) is classified according to the age of onset and severity of the clinical manifestations into: acute (Werding-Hoffman disease or type I), intermediate (type II) and juvenile (Kugelberg-Wilander disease or type III) forms. All three SMAs have been linked to markers at 5q11.2-q13.3. Two candidate genes deleted in SMA patients are the survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene. We have performed molecular analyses of these genes in 30 unrelated Macedonian families (17 with type I, eight with type II and five with type III forms of the disease). Deletions of exons 7 and 8 of the SMN gene were found in 76.6% (23/30) of patients (94.1% in type I, 87.5% in type II). Among these 23 families, 19 had both exons deleted, while four had deletions only of exon 7. Deletions of exon 5 of the NAIP gene were found in 41.2% (7/17) patients with type I SMA and in 12.5% (1/8) of patients with type II SMA. No deletions of the SMN gene were found in 30 parents and 30 normal controls. We found 2/30 (6.7%) parents to be homozygous for the deletion of exon 5. Our data support the hypothesis that the telomeric SMN gene plays a major role in determining the clinical course of the disease, while the defects in the NAIP gene have only a modifying effect on the phenotype.

Nonsense-mediated messenger RNA decay of survival motor neuron 1 causes spinal muscular atrophy

2008 ◽  
Vol 123 (2) ◽  
pp. 141-153 ◽  
Author(s):  
Lars Brichta ◽  
Lutz Garbes ◽  
Maria Jedrzejowska ◽  
Sushma-Nagaraja Grellscheid ◽  
Irmgard Holker ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Messenger Rna ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Rna Decay ◽  
Messenger Rna Decay

scholarly journals Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy cells

2015 ◽  
Vol 4 ◽  
pp. 351-356 ◽  
Author(s):  
Nur Imma Fatimah Harahap ◽  
Dian Kesumapramudya Nurputra ◽  
Mawaddah Ar Rochmah ◽  
Ai Shima ◽  
Naoya Morisada ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Protein Degradation ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Survival Motor Neuron Protein ◽  
Motor Neuron Protein

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

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.

scholarly journals AAV9-mediated delivery of miR-23a reduces disease severity in Smn2B/−SMA model mice

2019 ◽  
Vol 28 (19) ◽  
pp. 3199-3210 ◽  
Author(s):  
Kevin A Kaifer ◽  
Eric Villalón ◽  
Benjamin S O'Brien ◽  
Samantha L Sison ◽  
Caley E Smith ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Viral Vector ◽  
Muscular Atrophy ◽  
Induced Pluripotent Stem Cell ◽  
Survival Motor Neuron ◽  
Virus Serotype

Abstract Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in survival motor neuron 1 (SMN1). The molecular mechanisms underlying motor neuron degeneration in SMA remain elusive, as global cellular dysfunction obscures the identification and characterization of disease-relevant pathways and potential therapeutic targets. Recent reports have implicated microRNA (miRNA) dysregulation as a potential contributor to the pathological mechanism in SMA. To characterize miRNAs that are differentially regulated in SMA, we profiled miRNA levels in SMA induced pluripotent stem cell (iPSC)-derived motor neurons. From this array, miR-23a downregulation was identified selectively in SMA motor neurons, consistent with previous reports where miR-23a functioned in neuroprotective and muscle atrophy-antagonizing roles. Reintroduction of miR-23a expression in SMA patient iPSC-derived motor neurons protected against degeneration, suggesting a potential miR-23a-specific disease-modifying effect. To assess this activity in vivo, miR-23a was expressed using a self-complementary adeno-associated virus serotype 9 (scAAV9) viral vector in the Smn2B/− SMA mouse model. scAAV9-miR-23a significantly reduced the pathology in SMA mice, including increased motor neuron size, reduced neuromuscular junction pathology, increased muscle fiber area, and extended survival. These experiments demonstrate that miR-23a is a novel protective modifier of SMA, warranting further characterization of miRNA dysfunction in SMA.

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