ArticleHuman molecular genetics2017
Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 47 citations in OpenAlex.
- Survival motor neuron protein-independent amelioration of spinal muscular atrophy by pharmacological inhibition of c-Jun-NHBrain communications · 2026Article
- Novel Translational Concept: Axon-to-Muscle Exosomal Signaling as an Emerging Therapeutic Target in Spinal Muscular Atrophy.Biomedicines · 2025Review
- Temporal transcriptomic profiling of human three-dimensional neuromuscular co-cultures.Biology open · 2025Article
- Review
- Treating neuromuscular diseases: unveiling gene therapy breakthroughs and pioneering future applications.Journal of biomedical science · 2025Review
- Recent Progress in Gene-Targeting Therapies for Spinal Muscular Atrophy: Promises and Challenges.Genes · 2024Review
- Beyond Motor Neurons in Spinal Muscular Atrophy: A Focus on Neuromuscular Junction.International journal of molecular sciences · 2024Review
- Neural Isoforms of Agrin Are Generated by Reduced PTBP1-RNA Interaction Network Spanning the Neuron-Specific Splicing Regions inInternational journal of molecular sciences · 2023Article
- Curing SMA: Are we there yet?Gene therapy · 2023Review
- The SMN Complex at the Crossroad between RNA Metabolism and Neurodegeneration.International journal of molecular sciences · 2023Review
- A link between agrin signalling and CaScientific reports · 2022Article
- SMN controls neuromuscular junction integrity through U7 snRNP.Cell reports · 2022Article
- Neuromuscular denervation and deafferentation but not motor neuron death are disease features in the Smn2B/- mouse model of SMA.PloS one · 2022Article
- Central synaptopathy is the most conserved feature of motor circuit pathology across spinal muscular atrophy mouse models.iScience · 2021Article
- Emerging concepts underlying selective neuromuscular dysfunction in infantile-onset spinal muscular atrophy.Neural regeneration research · 2021Review
- Activation of Muscle-Specific Kinase (MuSK) Reduces Neuromuscular Defects in the Delta7 Mouse Model of Spinal Muscular Atrophy (SMA).International journal of molecular sciences · 2021Article
- Spinal muscular atrophy: From approved therapies to future therapeutic targets for personalized medicine.Cell reports. Medicine · 2021Review
- Chronic Pharmacological Increase of Neuronal Activity Improves Sensory-Motor Dysfunction in Spinal Muscular Atrophy Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- AAV9-DOK7 gene therapy reduces disease severity in SmnBiochemical and biophysical research communications · 2020Article
- New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges.Journal of clinical medicine · 2020Review
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Authors and funding
5 authors at 2 institutions in 3 countries.
Funding
Abstract
Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure. In this study, we explore the effects of one such transcript-Z+Agrin-known to be a critical organizer of the NMJ. We confirm that low SMN protein reduces motor neuronal levels of Z+Agrin. Repletion of this isoform of Agrin in the motor neurons of SMA model mice increases muscle fiber size, enhances the post-synaptic NMJ area, reduces the abnormal accumulation of intermediate filaments in nerve terminals of the neuromuscular synapse and improves the innervation of muscles. While these effects are independent of changes in SMN levels or increases in motor neuron numbers they nevertheless have a significant effect on the overall disease phenotype, enhancing mean survival in severely affected SMA model mice by ∼40%. We conclude that Agrin is an important target of the SMN protein and that mitigating NMJ defects may be one strategy in treating human spinal muscular atrophy.
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