Article

SMN Deficiency Causes Tissue-Specific Perturbations in the Repertoire of snRNAs and Widespread Defects in Splicing

Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6148, USA.
Cell (Impact Factor: 32.24). 06/2008; 133(4):585-600. DOI: 10.1016/j.cell.2008.03.031
Source: PubMed

ABSTRACT

The survival of motor neurons (SMN) protein is essential for the biogenesis of small nuclear RNA (snRNA)-ribonucleoproteins (snRNPs), the major components of the pre-mRNA splicing machinery. Though it is ubiquitously expressed, SMN deficiency causes the motor neuron degenerative disease spinal muscular atrophy (SMA). We show here that SMN deficiency, similar to that which occurs in severe SMA, has unexpected cell type-specific effects on the repertoire of snRNAs and mRNAs. It alters the stoichiometry of snRNAs and causes widespread pre-mRNA splicing defects in numerous transcripts of diverse genes, preferentially those containing a large number of introns, in SMN-deficient mouse tissues. These findings reveal a key role for the SMN complex in RNA metabolism and in splicing regulation and indicate that SMA is a general splicing disease that is not restricted to motor neurons.

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    • "Mutations that reduce the level of SMN proteins, which are involved in snRNP biogenesis, cause SMA. Although multiple alternative splicing defects have been noted, it remains unclear which splicing abnormalities cause the human phenotypes (Ule et al., 2005; Zhang et al., 2008 Fogel et al., 2012; Highley et al., 2014). As the SMN protein deficiency can be rescued by stimulating exon 7 inclusion in the SMN2 pre-mRNA, efforts deployed to achieve this goal in mouse models have produced encouraging results using oligonucleotides that block the activity of an intron splicing silencer (Hua et al., 2015; Staropoli et al., 2015) or small molecules that stimulate exon 7 inclusion with apparent high specificity (Naryshkin et al., 2014; Palacino et al., 2015). "

    Full-text · Article · Jan 2016 · The Journal of Cell Biology
    • "of research, the specific sensitivity of motor neurons to defects of the ubiquitous SMN protein that is involved in essential cell processes such as mRNA metabolism (Fischer et al., 1997; Pellizzoni et al., 1998) remains poorly understood. Microarray analyses unexpectedly failed to identify the specific misexpression of some essential genes in motor neurons after SMN depletion (Zhang et al., 2008). This may suggest that the selective degeneration of motor neurons in SMA results from alterations of systemic pathways that would ultimately target motor neurons. "
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    ABSTRACT: Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by the selective loss of spinal motor neurons due to the depletion of the survival of motor neuron (SMN) protein. No therapy is currently available for SMA, which represents the leading genetic cause of death in childhood. In the present study, we report that insulin-like growth factor-1 receptor (Igf-1r) gene expression is enhanced in the spinal cords of SMA-like mice. The reduction of expression, either at the physiological (through physical exercise) or genetic level, resulted in the following: (1) a significant improvement in lifespan and motor behavior, (2) a significant motor neuron protection, and (3) an increase in SMN expression in spinal cord and skeletal muscles through both transcriptional and posttranscriptional mechanisms. Furthermore, we have found that reducing IGF-1R expression is sufficient to restore intracellular signaling pathway activation profile lying downstream of IGF-1R, resulting in both the powerful activation of the neuroprotective AKT/CREB pathway and the inhibition of the ERK and JAK pathways. Therefore, reducing rather than enhancing the IGF-1 pathway could constitute a useful strategy to limit neurodegeneration in SMA.
    No preview · Article · Aug 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    • "Regarding function, a number of studies have clearly demonstrated that FL-SMN is part of a macromolecular complex playing a fundamental role in spliceosomal biogenesis and mRNA splicing151617181920. However, it is not as yet clear whether impairment of splicing is the key pathogenic step leading to SMA21222324. FL-SMN has been localized in axons and growth cones of developing motor neurons252627, and several studies have suggested a role for FL-SMN in the axonal transport of mRNAs28293031. Thus, the loss of this specific function might lead to the motor neuron failure typical of SMA[28]. "
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    ABSTRACT: The key pathogenic steps leading to spinal muscular atrophy (SMA), a genetic disease characterized by selective motor neuron degeneration, are not fully clarified. The full-length SMN protein (FL-SMN), the main protein product of the disease gene SMN1, plays an established role in the cytoplasm in snRNP biogenesis ultimately leading to mRNA splicing within the nucleus. It is also involved in the mRNA axonal transport. However, to what extent the impairment of these two SMN functions contributes to SMA pathogenesis remains unknown. A shorter SMN isoform, axonal-SMN or a-SMN, with more specific axonal localization, has been discovered, but whether it might act in concert with FL-SMN in SMA pathogenesis is not known. As a first step in defining common or divergent intracellular roles of FL-SMN vs a-SMN proteins, we here characterized the turn-over of both proteins and investigated which pathway contributed to a-SMN degradation. We performed real time western blot and confocal immunofluorescence analysis in easily controllable in vitro settings. We analyzed co-transfected NSC34 and HeLa cells and cell clones stably expressing both a-SMN and FL-SMN proteins after specific blocking of transcript or protein synthesis and inhibition of known intracellular degradation pathways. Our data indicated that whereas the stability of both FL-SMN and a-SMN transcripts was comparable, the a-SMN protein was characterized by a much shorter half-life than FL-SMN. In addition, as already demonstrated for FL-SMN, the Ub/proteasome pathway played a major role in the a-SMN protein degradation. We hypothesize that the faster degradation rate of a-SMN vs FL-SMN is related to the protection provided by the protein complex in which FL-SMN is assembled. The diverse a-SMN vs FL-SMN C-terminus may dictate different protein interactions and complex formation explaining the different localization and role in the neuronal compartment, and the lower expression and stability of a-SMN.
    Full-text · Article · Jul 2015 · PLoS ONE
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