Article

Inactivation of the SMN Complex by Oxidative Stress

Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6148, USA.
Molecular cell (Impact Factor: 14.46). 07/2008; 31(2):244-54. DOI: 10.1016/j.molcel.2008.06.004
Source: PubMed

ABSTRACT The SMN complex is essential for the biogenesis of small nuclear ribonucleoproteins (snRNPs), the major constituents of the spliceosome. Deficiency in functional SMN protein causes spinal muscular atrophy, a common motor neuron degenerative disease of severity commensurate with SMN levels and, correspondingly, snRNP assembly decreases. We developed a high-throughput screen for snRNP assembly modifiers and discovered that reactive oxygen species (ROS) inhibit SMN-complex activity in a dose-dependent manner. ROS-generating compounds, e.g., the environmental toxins menadione and beta-lapachone (in vivo IC(50) = 0.45 muM) also cause intermolecular disulfide crosslinking of SMN. Both the oxidative inactivation and SMN crosslinking can be reversed by reductants. We identified two cysteines that form SMN-SMN disulfide crosslinks, defining specific contact points in oligomeric SMN. Thus, the SMN complex is a redox-sensitive assemblyosome and an ROS target, suggesting that it may play a role in oxidative stress pathophysiology, which is associated with many degenerative diseases.

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    • "The splicing changes that we uncovered in SMN2 transgene transcripts during late stage SMA were not described in these studies, although in other studies, SMN2 splicing was shown to decrease in type I mice at P1 (Jodelka et al. 2010; Ruggiu et al. 2012). Dying mice likely suffer from hypoxia; hypoxic stress induces reactive oxygen species generation, which inactivates the SMN complex (Wan et al. 2008). This complex plays fundamental roles in assembling snRNPs, which are required for splicing (Burghes and Beattie 2009), and low SMN levels result in decreased SMN2 exon 7 splicing through a feedback loop (Jodelka et al. 2010; Ruggiu et al. 2012). "
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    • "This is particularly well demonstrated in ALS, where both sporadic and familial forms share the same symptoms and pathological phenotype, that are recapitulated in available animal and cell models, with a prominent role for mitochondrial damage and resulting oxidative stress (for an extended Review, see [25]). Oxidative stress is reported also in SMA [26] and reactive oxygen species (ROS) inhibit assembly and activity of SMN complex in a dose-dependent manner [27]. Mitochondrial damage seems to be invariably present in neurodegenerative conditions [28] including SMA [29] [30] [31] [32] and SBMA [33], in which mitochondrial dysfunction may be due to the interaction between AR and cytochrome c oxidase subunit Vb (COXVb) [34]. "
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