A survey of transcripts generated by spinal muscular atrophy genes
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Spinal muscular atrophy (SMA) is a frequenct autosomal recessive disease characterized by motor neuron degeneration. The recently identified survival motor neuron (SMN) gene is the essential gene responsible for the SMA phenotype. The SMN protein is a complex molecule with several proposed functions, including a key role in pre-mRNAs maturation and splicing, which however do not fully explain the selective motor neuron death typical of SMA. Although widely distributed in neural and non-neural tissues, SMN is however highly expressed in motor neurons during ontogenesis to adulthood, indicating that motor neurons are strictly SMN-dependent for their function and survival from early phases of development to mature stages. Studies on the subcellular localization, protein isoforms and from animal models are likely to shed further light on the functional role of the protein, and to help defining appropriate therapeutic approachs for SMA patients.
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Spinal muscular atrophy (SMA) is a frequenct autosomal recessive disease characterized by motor neuron degeneration. The recently identified survival motor neuron (SMN) gene is the essential gene responsible for the SMA phenotype. The SMN protein is a complex molecule with several proposed functions, including a key role in pre-mRNAs maturation and splicing, which however do not fully explain the selective motor neuron death typical of SMA. Although widely distributed in neural and non-neural tissues, SMN is however highly expressed in motor neurons during ontogenesis to adulthood, indicating that motor neurons are strictly SMN-dependent for their function and survival from early phases of development to mature stages. Studies on the subcellular localization, protein isoforms and from animal models are likely to shed further light on the functional role of the protein, and to help defining appropriate therapeutic approachs for SMA patients.
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Neuromuscular disease
Progressive muscular atrophy
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Muscle Atrophy
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Infantile-onset spinal muscular atrophy (SMA) is a prototypical disease in which to investigate selective neurodegenerative phenotypes. Caused by low levels of the ubiquitously expressed Survival Motor Neuron (SMN) protein, the disease mainly targets the spinal motor neurons. This selective phenotype remains largely unexplained, but has not hindered the development of SMN repletion as a means to a treatment. Here we chronicle recent advances in the area of SMA biology. We provide a brief background to the disease, highlight major advances that have shaped our current understanding of SMA, trace efforts to treat the condition, discuss the outcome of two promising new therapies and conclude by considering contemporary as well as new challenges stemming from recent successes within the field.
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Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease that predominantly affects motor neurons, resulting in progressive muscular atrophy and weakness. SMA arises due to insufficient survival motor neuron (SMN) protein levels as a result of homozygous disruption of the SMN1 gene. SMN upregulation is a promising and potent treatment strategy for this currently incurable condition. In this issue of the JCI, two independent research groups report novel observations in mouse models of severe SMA that provide hope that this approach will afford meaningful benefit to individuals with SMA.
SMN1
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Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in motor neurons only partially rescues SMA in mouse models, although it is thought to be therapeutically essential. Here, we address the relative importance of SMN restoration in the central nervous system (CNS) versus peripheral tissues in mouse models using a therapeutic splice-switching antisense oligonucleotide to restore SMN and a complementary decoy oligonucleotide to neutralize its effects in the CNS. Increasing SMN exclusively in peripheral tissues completely rescued necrosis in mild SMA mice and robustly extended survival in severe SMA mice, with significant improvements in vulnerable tissues and motor function. Our data demonstrate a critical role of peripheral pathology in the mortality of SMA mice and indicate that peripheral SMN restoration compensates for its deficiency in the CNS and preserves motor neurons. Thus, SMA is not a cell-autonomous defect of motor neurons in SMA mice.
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