A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity

Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Genes & development (Impact Factor: 12.64). 03/2010; 24(5):438-42. DOI: 10.1101/gad.1884910
Source: PubMed

ABSTRACT Spinal muscular atrophy (SMA) is caused by homozygous survival of motor neurons 1 (SMN1) gene deletions, leaving a duplicate gene, SMN2, as the sole source of SMN protein. However, most of the mRNA produced from SMN2 pre-mRNA is exon 7-skipped ( approximately 80%), resulting in a highly unstable and almost undetectable protein (SMNDelta7). We show that this splicing defect creates a potent degradation signal (degron; SMNDelta7-DEG) at SMNDelta7's C-terminal 15 amino acids. The S270A mutation inactivates SMNDelta7-DEG, generating a stable SMNDelta7 that rescues viability of SMN-deleted cells. These findings explain a key aspect of the SMA disease mechanism, and suggest new treatment approaches based on interference with SMNDelta7-DEG activity.

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    • "Moreover, several unstable proteins, ubiquitin and proteasomes have been localized to a subset of PML bodies (Lafarga et al. 2002; Lallemand-Breitenbach and de Thé 2010), suggesting a role of these structures in protein degradation by the proteasome in dysfunctional neurons (Salomoni and Betts-Henderson 2011). Accordingly, the increase in the PML body number might promote degradation of the mutant SMN7 protein by the proteasome (Cho and Dreyfuss 2010). The participation of the proteasome in regulating SMN levels is supported by the recent evidence that treatment with bortezomib, a proteasome inhibitor, increases SMN levels in tissues of a SMA model mouse (Kwon et al. 2011). "
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    ABSTRACT: Type I spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by loss or mutations of the survival motor neuron 1 (SMN1) gene. The reduction in SMN protein levels in SMA leads to degeneration and death of motor neurons. In this study, we have analyzed the nuclear reorganization of Cajal bodies, PML bodies and nucleoli in type I SMA motor neurons with homozygous deletion of exons 7 and 8 of the SMN1 gene. Western blot analysis revealed a marked reduction of SMN levels compared to the control sample. Using a neuronal dissociation procedure to perform a careful immunocytochemical and quantitative analysis of nuclear bodies, we demonstrated a severe decrease in the mean number of Cajal bodies per neuron and in the proportion of motor neurons containing these structures in type I SMA. Moreover, most Cajal bodies fail to recruit SMN and spliceosomal snRNPs, but contain the proteasome activator PA28γ, a molecular marker associated with the cellular stress response. Neuronal stress in SMA motor neurons also increases PML body number. The existence of chromatolysis and eccentric nuclei in SMA motor neurons correlates with Cajal body disruption and nucleolar relocalization of coilin, a Cajal body marker. Our results indicate that the Cajal body is a pathophysiological target in type I SMA motor neurons. They also suggest the Cajal body-dependent dysfunction of snRNP biogenesis and, therefore, pre-mRNA splicing in these neurons seems to be an essential component for SMA pathogenesis.
    Histochemie 02/2012; DOI:10.1007/s00418-012-0921-8 · 2.93 Impact Factor
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    • "In human, the SMN2 gene is almost identical to SMN1 but contains a C to T transition at position 6 in exon 7. This nucleotide change induces SMN2 exon 7 skipping during splicing and results in an unstable truncated SMN protein (Cho & Dreyfuss, 2010). Therefore, SMN2 fails to produce a sufficient amount of functional SMN protein to compensate for the loss of SMN1 (Lorson, et al., 1999; Monani, et al., 1999). "
    RNA Processing, 08/2011; , ISBN: 978-953-307-557-0
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    ABSTRACT: Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA results from deletions or mutations of survival motor neuron 1 (SMN1), an essential gene. SMN2, a nearly identical copy, can compensate for SMN1 loss if SMN2 exon 7 skipping is prevented. Among the many cis-elements involved in the splicing regulation of SMN exon 7, intronic splicing silencer N1 (ISS-N1) has emerged as the most effective target for an antisense oligonucleotide (ASO)-mediated splicing correction of SMN2 exon 7. Blocking of ISS-N1 by an ASO has been shown to fully restore SMN2 exon 7 inclusion in SMA patient cells as well as in vivo. Here we review how ISS-N1 targeting ASOs that use different chemistries respond differently in the various SMA mouse models. We also compare other ASO-based strategies for therapeutic splicing correction in SMA. Given that substantial progress on ASO-based strategies to promote SMN2 exon 7 inclusion in SMA has been made, and that similar approaches in a growing number of genetic diseases are possible, this report has wide implications.
    03/2013; 4(1). DOI:10.2478/s13380-013-0109-2
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