A study published in the journal PLoS One revealed that members from specific protein families could be potential new targets for spinal muscular atrophy (SMA) therapies. The study is entitled, “Targeting SR Proteins Improves SMN Expression in Spinal Muscular Atrophy Cells.”
SMA is a rare, devastating motor neuron disease and one of the leading genetic causes of pediatric mortality, with an incidence of 1 in 6,000 live births. It is characterized by the degeneration of nerves controlling muscles and voluntary movement, resulting in paralysis and eventually death. It currently has no approved treatment.
SMA results from a mutation or deletion in a gene called survival of motor neuron 1 (SMN1), causing insufficient production of the SMN protein. The SMN protein has two variants – SMN1 and SMN2. SMN2 is mainly produced as an unstable and shortened version of the SMN protein due to a single nucleotide difference in the exon 7 of the gene, and therefore cannot compensate for SMN1 loss. Only around 10% of SMN2 proteins produced are full-length (and therefore containing exon 7), and these are an important determinant of disease severity. Researchers have been studying the possibility of increasing SMN2 exon 7 inclusion, and subsequently SMN protein levels, as a therapeutic strategy for SMA.
Members of the serine/arginine (SR) splicing factor protein family and the heterogeneous ribonucleoprotein (hnRNP) family have been shown to influence exon 7 inclusion. Based on this knowledge, researchers decided to study the role of these two protein families in SMN2 exon 7 inclusion. By depletion or over-expression techniques, the team found that SRSF1 to SRSF7 proteins, plus SRSF11, hnRNPA1/B1 and hnRNP U could all inhibit exon 7 inclusion. In the absence of SRSF2 or SRSF3 (two strong inhibitors of exon 7 inclusion) in SMA patient-derived cell lines, there was an increase in exon 7 inclusion and subsequently of SMN protein levels.
Based on their findings, the team suggests that proteins that can influence or regulate SMN2 exon 7 inclusion may represent potential targets for future SMA therapies. In addition, researchers also suggest that some cell-types or tissues can present differences in the efficiency of SMN 2 exon 7 inclusion, where tissues with a greater exon 7 inclusion have higher levels of SMN protein, becoming protected from the defects associated with an insufficient SMN protein production.