Constitutive muscular abnormalities in culture in spinal muscular atrophy

doi:10.1016/S0140-6736(95)90869-2

The Lancet

Volume 345, Issue 8951, 18 March 1995, Pages 694-695

https://doi.org/10.1016/S0140-6736(95)90869-2 Get rights and content

Abstract

To explore the cause of spinal muscular atrophy (SMA), we used an in-vitro model of nerve-muscle co-cultures in which motoneurons were normal and satellite cells were obtained from SMA patients. In co-cultures initiated with satellite cells from type I and type II SMA patients only, we observed degeneration of the innervated fibres after 1-3 weeks of nerve-muscle co-culture. This process involved vacuolisation, disorganisation, and death of the innervated muscle fibres. This observation points to a muscular implication in the severe forms of SMAs.

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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.
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Spinal muscular atrophy (SMA) is a fatal neurologic disorder affecting most commonly children. It is characterized by motor neuron loss, muscle atrophy, and a panoply of other manifestations in non-neuronal tissues. It is caused by mutation or deletion in the Survival Motor Neuron (SMN) 1 gene, while a nearly identical gene, termed SMN2, mediates disease severity. Chromatin signaling in the context of SMA has never been systematically addressed. Yet, the SMN protein has an important function in the 3′ end mRNA processing of canonical histone transcripts and contains a Tudor domain capable of recognizing methylation marks at lysine 79 of histone H3 protein. Furthermore, SMN2 gene expression is regulated by methylation, acetylation, and long non-coding RNAs. Additionally, much effort in finding therapeutic options for SMA focused on histone deacetylase inhibitors, which can non-selectively increase SMN2 expression, and also act on off-target genes, or acetylate other proteins that might be important in SMA pathogenesis. Here, we review SMN protein functions in histone mRNA processing, its potential implication as an epigenetic player, the important epigenetic marks on SMN genes, and the success and failure of histone deacetylase inhibitors as therapeutic agents for SMA.
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Skeletal muscle is a form of striated muscle that provides vertebrates with locomotive ability, in addition to serving metabolic and endocrine roles in the organism. Although spinal muscular atrophy (SMA) is considered primarily a neuronal disorder, the substantial atrophy of muscle mass in affected individuals is a striking feature of the disease. With advancements in knowledge of both SMA pathology and skeletal muscle biology, skeletal muscle has emerged as a therapeutic target for SMA. This chapter reviews skeletal muscle physiology as it fits in the context of SMA pathology and therapeutic development.
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2017, Spinal Muscular Atrophy: Disease Mechanisms and Therapy
The neuromuscular junction (NMJ) is a specialized synapse, forming the primary connection between a lower motor neuron and a skeletal muscle fiber. Maintaining robust function of the NMJ is critical for healthy muscular contraction and movement, with disruption of the NMJ being recognized as an important and early pathological event in spinal muscular atrophy (SMA). This chapter provides an overview of evidence put forward from animal models and patient studies identifying core morphological and functional abnormalities present at the NMJ in SMA, including cytoskeletal disruption, deficient synaptic transmission, and nerve terminal retraction/degeneration. This chapter discusses the contribution of different cell types to NMJ pathology in SMA, evidence of developmental and maturation deficiencies contributing to disease pathogenesis, and advances in therapy development aimed at improving NMJ stability. Although the cellular and molecular pathways regulating NMJ pathology in SMA have yet to be fully revealed, the chapter discusses several biological processes that could contribute to NMJ degeneration in SMA.

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Constitutive muscular abnormalities in culture in spinal muscular atrophy

Abstract

Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3

Nature

De novo and inherited deletions of the 5q13 region in spinal muscular atrophies

Science