RESUMEN

Spinal muscular atrophy (SMA) is a severe genetic disorder characterized by the loss of motor neurons, leading to progressive muscle weakness, loss of mobility, and respiratory complications. In its most severe forms, SMA can result in death within the first two years of life if untreated. The condition arises from mutations in the SMN1 (survival of motor neuron 1) gene, causing a deficiency in the survival motor neuron (SMN) protein. Humans possess a near-identical gene, SMN2, which modifies disease severity and is a primary target for therapies. Recent therapeutic advancements include antisense oligonucleotides (ASOs), small molecules targeting SMN2, and virus-mediated gene replacement therapy delivering a functional copy of SMN1. Additionally, recognizing SMA's broader phenotype involving multiple organs has led to the development of SMN-independent therapies. Evidence now indicates that SMA affects multiple organ systems, suggesting the need for SMN-independent treatments along with SMN-targeting therapies. No single therapy can cure SMA; thus, combination therapies may be essential for comprehensive treatment. This review addresses the SMA etiology, the role of SMN, and provides an overview of the rapidly evolving therapeutic landscape, highlighting current achievements and future directions.

Asunto(s)

Terapia Genética , Atrofia Muscular Espinal , Oligonucleótidos Antisentido , Proteína 1 para la Supervivencia de la Neurona Motora , Proteína 2 para la Supervivencia de la Neurona Motora , Humanos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Terapia Genética/métodos , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Oligonucleótidos Antisentido/uso terapéutico , Oligonucleótidos Antisentido/genética , Animales , Marcación de Gen/métodos

RESUMEN

Spinal muscular atrophy (SMA) is a rare neuromuscular disease, which is characterized by the degeneration of motor neurons, leading to symmetrical muscle weakness and atrophy. Description of two novel SMN1 mutations (patient1: c.683T > A, p.Leu228Ter; patient2: c.347 T > C, p.Ile116 Thr). We reported two patients with SMN1 mutations with the clinical features, and provided a literature review of the previously reported 22 cases. Two SMA patients showed progressive proximal lower limb weakness and milder clinical symptom. In a total of 22 cases, the most commonly observed SMN1 gene alteration was missense mutation (55%), followed by splicing defect (27%), nonsense (9%) and frameshift (9%). We discuss the possible decisive role of these intragenic mutations in the phenotypic results, which enriched the SMN 1 fine mutation database.

RESUMEN

OBJECTIVE: Numerous studies have consistently found that reduced SMN protein expression does not severely affect cognitive function in SMA patients. However, the average intelligence quotient of SMA patients has ranged above to below average in different studies. The cognitive development of SMA patients identified through newborn screening remains largely unknown. METHODS: 40 of 47 eligible SMA patients (23 females/17 males) from 39 families identified through newborn screening between January 2018 and December 2020 underwent developmental testing using Bayley III (BSID) after the 2 years of age. The mean age was 29.25 months (23-42 months). 17 patients had 2, 11 patients had 3 and 12 patients had ≥4 copies of SMN2. RESULTS: cognitive scale: mean 94.55 (SD 24.01); language scale: mean 86.09 (SD 26.41); motor scale: 81.28 (SD 28.07). Overall, the cognitive scales show that 14 children were below average, 20 children were average and 6 children were above average. 10/14 children with below average scores had 2 SMN2 copies. The post-hoc pairwise comparisons showed that the cognition main scale was significantly more sensitive to the number of SMN2 copies than the motor main scale of the BSID (MΔ= 10.27, p = 0.014). There is also evidence that cognition scored higher than the language main scale (MΔ= 7.11, p = 0.090). CONCLUSION: The impaired cognitive development of SMA children with 2 SMN2 copies, despite early initiation of therapy, underscores the critical role of the SMN protein in the early stages of brain development.

Asunto(s)

Atrofia Muscular Espinal , Masculino , Niño , Recién Nacido , Femenino , Humanos , Preescolar , Tamizaje Neonatal , Procesamiento Proteico-Postraduccional

RESUMEN

Spinal Muscular Atrophy is a genetic neuromuscular disease that leads to muscle weakness and atrophy and it is characterized by the loss of α-motor neurons in the spinal cord's anterior horn cells. The disease appears due to low levels of the survival motor neuron protein. There are continuing clinical trials for the treatment of Spinal Muscular Atrophy. Quinazoline-based compounds are promising since they were tested on fibroblasts derived from the patients and found to increase the survival motor neuron protein levels. In this study, using multiple linear regression, we generated robust and valid quantitative structure- activity relationship models to predict the survival motor neuron-2 promoter activity of the new candidate compounds using the experimental survival motor neuron-2 promoter activity values of 2,4-diaminoquinazoline derivatives taken from the literature. The novel compounds designed by combining the pyrido[1,2-α]pyrimidin-4-one moeity of the known drug Risdiplam with that of 2,4 - diaminoquinazoline scaffold were predicted to exhibit strong promoter activities.

Asunto(s)

Atrofia Muscular Espinal , Relación Estructura-Actividad Cuantitativa , Humanos , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Neuronas Motoras/metabolismo , Quinazolinas/farmacología

RESUMEN

Biomolecular condensates (BMCs) can facilitate or inhibit diverse cellular functions. BMC formation is driven by noncovalent protein-protein, protein-RNA, and RNA-RNA interactions. Here, we focus on Tudor domain-containing proteins - such as survival motor neuron protein (SMN) - that contribute to BMC formation by binding to dimethylarginine (DMA) modifications on protein ligands. SMN is present in RNA-rich BMCs, and its absence causes spinal muscular atrophy (SMA). SMN's Tudor domain forms cytoplasmic and nuclear BMCs, but its DMA ligands are largely unknown, highlighting open questions about the function of SMN. Moreover, DMA modification can alter intramolecular interactions and affect protein localization. Despite these emerging functions, the lack of direct methods of DMA detection remains an obstacle to understanding Tudor-DMA interactions in cells.

Asunto(s)

Proteínas de Unión al ARN , ARN , Ligandos , Proteínas de Unión al ARN/metabolismo , Proteínas del Complejo SMN/metabolismo

RESUMEN

Spinal muscular atrophy (SMA) is caused by low levels of the survival of motoneuron (SMN) Protein leading to preferential degeneration of lower motoneurons in the ventral horn of the spinal cord and brain stem. However, the SMN protein is ubiquitously expressed and there is growing evidence of a multisystem phenotype in SMA. Since a loss of SMN function is critical, it is important to decipher the regulatory mechanisms of SMN function starting on the level of the SMN protein itself. Posttranslational modifications (PTMs) of proteins regulate multiple functions and processes, including activity, cellular trafficking, and stability. Several PTM sites have been identified within the SMN sequence. Here, we map the identified SMN PTMs highlighting phosphorylation as a key regulator affecting localization, stability and functions of SMN. Furthermore, we propose SMN phosphorylation as a crucial factor for intracellular interaction and cellular distribution of SMN. We outline the relevance of phosphorylation of the spinal muscular atrophy (SMA) gene product SMN with regard to basic housekeeping functions of SMN impaired in this neurodegenerative disease. Finally, we compare SMA patient mutations with putative and verified phosphorylation sites. Thus, we emphasize the importance of phosphorylation as a cellular modulator in a clinical perspective as a potential additional target for combinatorial SMA treatment strategies.

Asunto(s)

Atrofia Muscular Espinal , Enfermedades Neurodegenerativas , Animales , Modelos Animales de Enfermedad , Neuronas Motoras/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Fenotipo , Proteína 1 para la Supervivencia de la Neurona Motora/genética

RESUMEN

INTRODUCTION: Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disease which is characterised by muscle atrophy and early death in most patients. Risdiplam is the third overall and first oral drug approved for SMA with disease-modifying potential. Risdiplam acts as a survival motor neuron 2 (SMN2) pre-mRNA splicing modifier with satisfactory safety and efficacy profile. This review aims to critically appraise the place of risdiplam in the map of SMA therapeutics. AREAS COVERED: This review gives an overview of the current market for SMA and presents the mechanism of action and the pharmacological properties of risdiplam. It also outlines the development of risdiplam from early preclinical stages through to the most recently published results from phase 2/3 clinical trials. Risdiplam has proved its efficacy in pivotal trials for SMA Types 1, 2, and 3 with a satisfactory safety profile. EXPERT OPINION: In the absence of comparative data with the other two approved drugs, the role of risdiplam in the treatment algorithm of affected individuals is examined in three different patient populations based on the age and diagnosis method (newborn screening or clinical, symptom-driven diagnosis). Long-term data and real-world data will play a fundamental role in its future.

Asunto(s)

Atrofia Muscular Espinal , Compuestos Azo/efectos adversos , Humanos , Recién Nacido , Neuronas Motoras , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/genética , Pirimidinas , Empalme del ARN , Enfermedades Raras/tratamiento farmacológico , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/genética

RESUMEN

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and one of the most common genetic causes of infant death. It is characterized by progressive weakness of the muscles, loss of ambulation, and death from respiratory complications. SMA is caused by the homozygous deletion or mutations in the survival of the motor neuron 1 (SMN1) gene. Humans, however, have a nearly identical copy of SMN1 known as the SMN2 gene. The severity of the disease correlates inversely with the number of SMN2 copies present. SMN2 cannot completely compensate for the loss of SMN1 in SMA patients because it can produce only a fraction of functional SMN protein. SMN protein is ubiquitously expressed in the body and has a variety of roles ranging from assembling the spliceosomal machinery, autophagy, RNA metabolism, signal transduction, cellular homeostasis, DNA repair, and recombination. Motor neurons in the anterior horn of the spinal cord are extremely susceptible to the loss of SMN protein, with the reason still being unclear. Due to the ability of the SMN2 gene to produce small amounts of functional SMN, two FDA-approved treatment strategies, including an antisense oligonucleotide (AON) nusinersen and small-molecule risdiplam, target SMN2 to produce more functional SMN. On the other hand, Onasemnogene abeparvovec (brand name Zolgensma) is an FDA-approved adeno-associated vector 9-mediated gene replacement therapy that can deliver a copy of the human SMN1. In this review, we summarize the SMA etiology, the role of SMN, and discuss the challenges of the therapies that are approved for SMA treatment.

Asunto(s)

Atrofia Muscular Espinal , Homocigoto , Humanos , Lactante , Neuronas Motoras/metabolismo , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Oligonucleótidos Antisentido/uso terapéutico , Eliminación de Secuencia

RESUMEN

Spinal muscular atrophy (SMA) is an inherited disorder characterized by degeneration of motor neurons and symmetrical muscle weakness and atrophy. Moyamoya syndrome (MMS) or moyamoya disease (MMD) is radiologically defined by chronic cerebrovascular occlusion with abnormal vascular network formation in the skull base. We report herein a 21-year-old female patient with limb weakness and muscular atrophy for 17 years. Electromyography revealed extensive motor neuron damage. Cranial MRA showed occlusion of bilateral anterior and middle cerebral arteries, with increased peripheral blood vessels and collateral circulation. She was diagnosed as SMA type IIIb combined with MMS following genetic testing, in which homozygous deletion of exons 7 and 8 of survival motor neuron (SMN)1 gene and 3 copies of exons 7 and 8 of SMN2 gene were detected. After treatment, the patient's symptoms improved. Our study found that the rare SMA and MMS co-exist. We speculated that the moyamoya phenomenon may be related to the abnormal regulation of intracranial vascular endothelial cells and smooth muscle cells in proliferation and differentiation caused by functional defects of SMN protein. The relationship between the two diseases needs to be further elucidated in future clinical work.

RESUMEN

BACKGROUND: The introduction of a comprehensive newborn screening program for spinal muscular atrophy (SMA), specifically for 5q-SMA, is planned for the end of 2021 in Germany. Several targeted treatment options have become available for all patients with SMA. MATERIAL AND METHODS: Newborn screening for 5q-SMA is based on the detection of a homozygous deletion of exon 7 in the SMN1 gene by molecular genetic analysis from the dried blood card. In all cases a second blood sample must be drawn as a part of confirmation diagnostics including the determination of the SMN2 copy numbers. RESULTS: Insights from pilot projects performed in parts of Germany are presented. Advantages and disadvantages of the screening project are discussed. CONCLUSION: Consultation and treatment should be carried out in a department of neuropediatrics with experience in the treatment of children with 5q-SMA, which is able to provide all current treatment options for the child, so that, when necessary, the treatment can be started within the first month of life.

Asunto(s)

Atrofia Muscular Espinal , Tamizaje Neonatal , Niño , Exones , Homocigoto , Humanos , Recién Nacido , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Eliminación de Secuencia

RESUMEN

Autosomal-recessive spinal muscular atrophy (SMA) is characterized by the loss of specific motor neurons of the spinal cord and skeletal muscle atrophy. SMA is caused by mutations or deletions of the survival motor neuron 1 (SMN1) gene, and disease severity correlates with the expression levels of the nearly identical copy gene, SMN2. Both genes ubiquitously express SMN protein, but SMN2 generates only low levels of protein that do not fully compensate for the loss-of-function of SMN1. SMN protein forms a multiprotein complex essential for the cellular assembly of ribonucleoprotein particles involved in diverse aspects of RNA metabolism. Other studies using animal models revealed a spatio-temporal requirement of SMN that is high during the development of the neuromuscular system and later, in the general maintenance of cellular and tissues homeostasis. These observations define a period for maximum therapeutic efficiency of SMN restoration, and suggest that cells outside the central nervous system may also participate in the pathogenesis of SMA. Finally, recent innovative therapies have been shown to mitigate SMN deficiency and have been approved to treat SMA patients. We briefly review major findings from the past twenty-five years of SMA research. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Asunto(s)

Terapia Genética/métodos , Fármacos Neuromusculares/uso terapéutico , Atrofias Musculares Espinales de la Infancia/genética , Atrofias Musculares Espinales de la Infancia/terapia , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Animales , Biomarcadores/metabolismo , Marcadores Genéticos , Humanos , Mutación , ARN/metabolismo , Atrofias Musculares Espinales de la Infancia/metabolismo , Atrofias Musculares Espinales de la Infancia/fisiopatología , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/metabolismo

RESUMEN

Spinal muscular atrophy (SMA) is the leading genetic cause of death in young children, arising from homozygous deletion or mutation of the survival motor neuron 1 (SMN1) gene. SMN protein expressed from a paralogous gene, SMN2, is the primary genetic modifier of SMA; small changes in overall SMN levels cause dramatic changes in disease severity. Thus, deeper insight into mechanisms that regulate SMN protein stability should lead to better therapeutic outcomes. Here, we show that SMA patient-derived missense mutations in the Drosophila SMN Tudor domain exhibit a pronounced temperature sensitivity that affects organismal viability, larval locomotor function and adult longevity. These disease-related phenotypes are domain specific and result from decreased SMN stability at elevated temperature. This system was utilized to manipulate SMN levels during various stages of Drosophila development. Owing to a large maternal contribution of mRNA and protein, Smn is not expressed zygotically during embryogenesis. Interestingly, we find that only baseline levels of SMN are required during larval stages, whereas high levels of the protein are required during pupation. This previously uncharacterized period of elevated SMN expression, during which the majority of adult tissues are formed and differentiated, could be an important and translationally relevant developmental stage in which to study SMN function. Taken together, these findings illustrate a novel in vivo role for the SMN Tudor domain in maintaining SMN homeostasis and highlight the necessity for high SMN levels at crucial developmental time points that are conserved from Drosophila to humans.

Asunto(s)

Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Actividad Motora/fisiología , Atrofia Muscular Espinal/genética , Mutación Puntual/genética , Proteínas de Unión al ARN/genética , Temperatura , Animales , Cicloheximida/farmacología , Proteínas de Drosophila/química , Drosophila melanogaster/efectos de los fármacos , Larva/efectos de los fármacos , Larva/crecimiento & desarrollo , Longevidad/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Mutación Missense/genética , Fenotipo , Dominios Proteicos , Estabilidad Proteica/efectos de los fármacos , Pupa/efectos de los fármacos , Pupa/crecimiento & desarrollo , Proteínas de Unión al ARN/química

RESUMEN

INTRODUCTION: We sought to determine whether survival motor neuron (SMN) protein blood levels correlate with denervation and SMN2 copies in spinal muscular atrophy (SMA). METHODS: Using a mixed-effect model, we tested associations between SMN levels, compound muscle action potential (CMAP), and SMN2 copies in a cohort of 74 patients with SMA. We analyzed a subset of 19 of these patients plus four additional patients who had been treated with received gene therapy to examine SMN trajectories early in life. RESULTS: Patients with SMA who had lower CMAP values had lower circulating SMN levels (P = .04). Survival motor neuron protein levels were different between patients with two and three SMN2 copies (P < .0001) and between symptomatic and presymptomatic patients (P < .0001), with the highest levels after birth and progressive decline over the first 3 years. Neither nusinersen nor gene therapy clearly altered SMN levels. DISCUSSION: These data provide evidence that whole blood SMN levels correlate with SMN2 copy number and severity of denervation.

Asunto(s)

Potenciales de Acción/fisiología , Músculo Esquelético/fisiopatología , Atrofia Muscular Espinal/sangre , Proteína 1 para la Supervivencia de la Neurona Motora/sangre , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/fisiopatología , Índice de Severidad de la Enfermedad

RESUMEN

Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease with an autosomal recessive trait of inheritance and great variability of its clinical course - from the lethal congenital type (SMA0) to the adult-onset form (SMA4). The disease is associated with a deficiency of SMN protein, which is encoded by two genes SMN1 and SMN2. Clinical symptoms depend on mutations in the SMN1 gene. The number of copies of twin similar SMN2 gene, which produces small amounts of SMN protein, is the main phenotype modifier, which determines the clinical severity of the disease. Until recently, it was considered that spinal cord motoneurons undergo selective loss. Recent studies have shown the role of SMN protein in various cellular processes and the multisystemic character of SMA. The aim of the therapeutic strategies developed so far has been to increase the expression of SMN protein by modifying the splicing of SMN2 gene (intrathecally administered antisense oligonucleotide - nusinersen; orally available small molecules: RG7916 and LMI070 or SMN1 gene replacement therapy (AAV9-SMN). The first SMN2-directed antisense oligonucleotide (nusinersen) has demonstrated in clinical trials high efficiency, and it has now been registered. The best effects were obtained in patients who were introduced to the drug in the pre symptomatic period. Studies on other substances are ongoing. The great advances in SMA therapy and increased understanding of the pathogenesis of the disease raise hopes for changes to the natural history of the disease. Simultaneously, it increases awareness of the need to improve the standard of patient care and early diagnosis (newborn screening). Many questions (e.g. emerging phenotypes, combined therapies, systemic vs. intrathecal administration, long-term consequences, and complications of the therapy) will require further studies and observations.

Asunto(s)

Atrofia Muscular Espinal , Humanos , Recién Nacido , Mutación , Fenotipo

RESUMEN

Spinal muscular atrophy (SMA) is a rare genetic and progressively debilitating neuromuscular disease. It is the leading genetic cause of death among infants. In SMA, low levels of survival of motor neuron (SMN) protein lead to motor neuron death and muscle atrophy as the SMN protein is critical to motor neuron survival. SMA is caused by mutations in, or deletion of, the SMN1 gene. A second SMN gene, SMN2, produces only low levels of functional SMN protein due to alternative splicing which excludes exon 7 from most transcripts, generating truncated, rapidly degraded SMN protein. Patients with SMA rely on limited expression of functional SMN full-length protein from the SMN2 gene, but insufficient levels are generated. RG7800 is an oral, selective SMN2 splicing modifier designed to modulate alternative splicing of SMN2 to increase the levels of functional SMN protein. In two trials, oral administration of RG7800 increased in blood full-length SMN2 mRNA expression in healthy adults and SMN protein levels in SMA patients by up to two-fold, which is expected to provide clinical benefit.

Asunto(s)

Atrofia Muscular Espinal/sangre , Atrofia Muscular Espinal/tratamiento farmacológico , Fármacos Neuromusculares/uso terapéutico , Pirazinas/uso terapéutico , Pirimidinas/uso terapéutico , Administración Oral , Adolescente , Adulto , Empalme Alternativo/efectos de los fármacos , Niño , Preescolar , Método Doble Ciego , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Atrofia Muscular Espinal/genética , Fármacos Neuromusculares/sangre , Pirazinas/sangre , Pirimidinas/sangre , ARN Mensajero/sangre , Proteína 2 para la Supervivencia de la Neurona Motora/sangre , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Adulto Joven

RESUMEN

Spinal muscular atrophy (SMA) is a rare, inherited neuromuscular disease caused by deletion and/or mutation of the Survival of Motor Neuron 1 (SMN1) gene. A second gene, SMN2, produces low levels of functional SMN protein that are insufficient to fully compensate for the lack of SMN1. Risdiplam (RG7916; RO7034067) is an orally administered, small-molecule SMN2 pre-mRNA splicing modifier that distributes into the central nervous system (CNS) and peripheral tissues. To further explore risdiplam distribution, we assessed in vitro characteristics and in vivo drug levels and effect of risdiplam on SMN protein expression in different tissues in animal models. Total drug levels were similar in plasma, muscle, and brain of mice (n = 90), rats (n = 148), and monkeys (n = 24). As expected mechanistically based on its high passive permeability and not being a human multidrug resistance protein 1 substrate, risdiplam CSF levels reflected free compound concentration in plasma in monkeys. Tissue distribution remained unchanged when monkeys received risdiplam once daily for 39 weeks. A parallel dose-dependent increase in SMN protein levels was seen in CNS and peripheral tissues in two SMA mouse models dosed with risdiplam. These in vitro and in vivo preclinical data strongly suggest that functional SMN protein increases seen in patients' blood following risdiplam treatment should reflect similar increases in functional SMN protein in the CNS, muscle, and other peripheral tissues.

Asunto(s)

Compuestos Azo/farmacocinética , Atrofia Muscular Espinal/tratamiento farmacológico , Fármacos Neuromusculares/farmacocinética , Pirimidinas/farmacocinética , Empalme del ARN/efectos de los fármacos , Proteína 2 para la Supervivencia de la Neurona Motora/metabolismo , Animales , Compuestos Azo/líquido cefalorraquídeo , Compuestos Azo/farmacología , Compuestos Azo/uso terapéutico , Encéfalo/metabolismo , Encéfalo/patología , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Exones/efectos de los fármacos , Exones/genética , Femenino , Humanos , Macaca fascicularis , Células de Riñón Canino Madin Darby , Masculino , Ratones , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Fármacos Neuromusculares/líquido cefalorraquídeo , Fármacos Neuromusculares/farmacología , Fármacos Neuromusculares/uso terapéutico , Pirimidinas/líquido cefalorraquídeo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas , Ratas Wistar , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Porcinos , Distribución Tisular

RESUMEN

Findings from mice that had their Smn gene deleted and some copies of the human SMN2 gene introduced to produce SMN protein are summarized. Symptoms due to this manipulation can be corrected only by restoring the SMN protein expression in neurones and not in muscle. The changes in muscle and neuromuscular junction (NMJ) in these mutant mice are probably due to the malfunction of the neuronal component of the NMJ i.e. the nerve terminal. The reduction of transmitter release by nerve terminals in animals with reduced SMN protein supports this notion. There is a critical period during which the presence of the SMN protein is mandatory for the survival of the motor unit and the individual. This period coincides with the most important events involved in the development of the motor unit. Results from normal genetically unaffected rats and mice show that during a critical period of development the function of the nerve terminal and the release of transmitter play a crucial role in the development of the motor neurone and muscle. The possibility that targeting the function of the nerve terminal to overcome its inability to release transmitter could benefit patients with the deletion of the SMN gene.

Asunto(s)

Neuronas Motoras/fisiología , Músculo Esquelético/crecimiento & desarrollo , Atrofia Muscular Espinal/fisiopatología , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Músculo Esquelético/fisiopatología , Atrofia Muscular Espinal/genética , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/genética

RESUMEN

Exercise studies in neuromuscular diseases like spinal muscular atrophy (SMA), a devastating disease caused by survival of motor neuron 1 ( SMN1) gene mutations, are drawing attention due to its beneficial effects. In this study, we presented a constructed arm cycling exercise protocol and evaluated the benefits on SMA patients. Five SMA type II patients performed 12 weeks of supervised arm cycling exercise. The physical functions were evaluated together with the SMN2 copy numbers, SMN protein levels, insulin-like growth factor 1(IGF1) and binding protein 3 (IGFBP3) levels. The active cycling distance and duration of patients significantly improved. Significant changes could not have detected either SMN or IGF1 and IGFBP3 levels in response to exercise. The findings demonstrated that the patients tolerated the exercise protocol and gained a benefit from arm cycling but benefits could not be associated with SMN2 copy number, SMN protein level, IGF1, or IGFBP3 levels.

Asunto(s)

Brazo/fisiopatología , Terapia por Ejercicio , Atrofias Musculares Espinales de la Infancia/fisiopatología , Atrofias Musculares Espinales de la Infancia/terapia , Biomarcadores/sangre , Niño , Preescolar , Terapia por Ejercicio/métodos , Dosificación de Gen , Expresión Génica , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Proyectos Piloto , Atrofias Musculares Espinales de la Infancia/genética , Proteína 2 para la Supervivencia de la Neurona Motora/sangre , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Resultado del Tratamiento

RESUMEN

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by degeneration of spinal motor neurons resulting in variable degrees of muscular wasting and weakness. It is caused by a loss-of-function mutation in the survival motor neuron (SMN1) gene. Caenorhabditis elegans mutants lacking SMN recapitulate several aspects of the disease including impaired movement and shorted life span. We examined whether genes previously implicated in life span extension conferred benefits to C. elegans lacking SMN. We find that reducing daf-2/insulin receptor signaling activity promotes survival and improves locomotor behavior in this C. elegans model of SMA. The locomotor dysfunction in C. elegans lacking SMN correlated with structural and functional abnormalities in GABAergic neuromuscular junctions (NMJs). Moreover, we demonstrated that reduction in daf-2 signaling reversed these abnormalities. Remarkably, enhancing GABAergic neurotransmission alone was able to correct the locomotor dysfunction. Our work indicated that an imbalance of excitatory/inhibitory activity within motor circuits and underlies motor system dysfunction in this SMA model. Interventions aimed at restoring the balance of excitatory/inhibitory activity in motor circuits could be of benefit to individuals with SMA.

Asunto(s)

Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/terapia , Atrofia Muscular Espinal/complicaciones , Ácido gamma-Aminobutírico/metabolismo , Adyuvantes Inmunológicos/farmacología , Animales , Animales Modificados Genéticamente , Fenómenos Biomecánicos/efectos de los fármacos , Fenómenos Biomecánicos/genética , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Inhibidores de la Colinesterasa/farmacología , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Trastornos Neurológicos de la Marcha/patología , Levamisol/farmacología , Longevidad/efectos de los fármacos , Longevidad/genética , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Unión Neuromuscular/efectos de los fármacos , Unión Neuromuscular/patología , Bromuro de Piridostigmina/farmacología , Interferencia de ARN/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Análisis de Supervivencia , Proteína 1 para la Supervivencia de la Neurona Motora/genética

RESUMEN

Spinal muscular atrophy (SMA) is a devastating motor neuron disease caused by mutations of the survival motor neuron 1 (SMN1) gene. SMN2, a paralogous gene to SMN1, can partially compensate for the loss of SMN1. On the basis of age at onset, highest motor function and SMN2 copy numbers, childhood-onset SMA can be divided into three types (SMA I-III). An inverse correlation was observed between SMN2 copies and the differential phenotypes of SMA. Interestingly, this correlation is not always absolute. Using SMA induced pluripotent stem cells (iPSCs), we found that the SMN was significantly decreased in both SMA III and SMA I iPSCs derived postmitotic motor neurons (pMNs) and γ-aminobutyric acid (GABA) neurons. Moreover, the significant differences of SMN expression level between SMA III (3 copies of SMN2) and SMA I (2 copies of SMN2) were observed only in pMNs culture, but not in GABA neurons or iPSCs. From these findings, we further discovered that the neurite outgrowth was suppressed in both SMA III and SMA I derived MNs. Meanwhile, the significant difference of neurite outgrowth between SMA III and SMA I group was also found in long-term cultures. However, significant hyperexcitability was showed only in SMA I derived mature MNs, but not in SMA III group. Above all, we propose that SMN protein is a major factor of phenotypic modifier. Our data may provide a new insight into recognition for differential phenotypes of SMA disease.

Asunto(s)

Células Madre Pluripotentes Inducidas/citología , Neuronas Motoras/citología , Neuronas Motoras/metabolismo , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patología , Fenotipo , Biomarcadores , Diferenciación Celular , Reprogramación Celular , Fenómenos Electrofisiológicos , Femenino , Neuronas GABAérgicas/metabolismo , Humanos , Immunoblotting , Inmunohistoquímica , Masculino , Atrofia Muscular Espinal/genética , Mutación , Neuritas/metabolismo , Linaje , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo