Abstract
Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by decreased levels of the survival of motoneuron (SMN) protein. Post-translational mechanisms for regulation of its stability are still elusive. Thus, we aimed to identify regulatory phosphorylation sites that modulate function and stability. Our results show that SMN residues S290 and S292 are phosphorylated, of which SMN pS290 has a detrimental effect on protein stability and nuclear localization. Furthermore, we propose that phosphatase and tensin homolog (PTEN), a novel phosphatase for SMN, counteracts this effect. In light of recent advancements in SMA therapies, a significant need for additional approaches has become apparent. Our study demonstrates S290 as a novel molecular target site to increase the stability of SMN. Characterization of relevant kinases and phosphatases provides not only a new understanding of SMN function, but also constitutes a novel strategy for combinatorial therapeutic approaches to increase the level of SMN in SMA.
Highlights
Spinal Muscular Atrophy (SMA) is a neuromuscular disease characterized by loss of motoneurons in the brain stem and spinal cord and caused by deletion or mutation of the survival of motoneuron 1Cells 2020, 9, 2405; doi:10.3390/cells9112405 www.mdpi.com/journal/cells (SMN1) gene [1]
Tryptic digestion of SMN resulted in long peptides, which could not be analyzed by mass spectrometry (MS)
To analyze the consequences of impaired stability mediated by phosphorylation of the single amino acid residue S290 in a cellular context, we studied the number of SMN-positive nuclear bodies (NBs)
Summary
Spinal Muscular Atrophy (SMA) is a neuromuscular disease characterized by loss of motoneurons in the brain stem and spinal cord and caused by deletion or mutation of the survival of motoneuron 1Cells 2020, 9, 2405; doi:10.3390/cells9112405 www.mdpi.com/journal/cells (SMN1) gene [1]. Spinal Muscular Atrophy (SMA) is a neuromuscular disease characterized by loss of motoneurons in the brain stem and spinal cord and caused by deletion or mutation of the survival of motoneuron 1. The SMN2 gene is highly similar but contains mutations leading to exclusion of exon 7 during pre-mRNA splicing [2]. The resulting truncated protein is unstable and cannot rescue the loss of SMN1 [2,3]. Copy number variation of SMN2 can increase the amount of functional SMN protein [5] and leads to milder forms of the disease (SMA types II, III, and IV). Therapies have been approved very recently that include splicing correction of SMN2 by an antisense-based approach and gene replacement therapy by systemic administration of an adeno-associated virus (AAV9) system coding for full-length SMN [6,7,8].
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