| First Author | Anderton RS | Year | 2012 |
| Journal | Neuroscience | Volume | 220 |
| Pages | 228-36 | PubMed ID | 22732506 |
| Mgi Jnum | J:192514 | Mgi Id | MGI:5465270 |
| Doi | 10.1016/j.neuroscience.2012.06.042 | Citation | Anderton RS, et al. (2012) Co-regulation of survival of motor neuron and Bcl-xL expression: implications for neuroprotection in spinal muscular atrophy. Neuroscience 220:228-36 |
| abstractText | Spinal muscular atrophy (SMA), a fatal genetic motor disorder of infants, is caused by diminished full-length survival of motor neuron (SMN) protein levels. Normally involved in small nuclear ribonucleoprotein (snRNP) assembly and pre-mRNA splicing, recent studies suggest that SMN plays a critical role in regulating apoptosis. Interestingly, the anti-apoptotic Bcl-x isoform, Bcl-xL, is reduced in SMA. In a related finding, Sam68, an RNA-binding protein, was found to modulate splicing of SMN and Bcl-xL transcripts, promoting SMNDelta7 and pro-apoptotic Bcl-xS transcripts. Here we demonstrate that Bcl-xL expression increases SMN protein by approximately 2-fold in SH-SY5Y cells. Conversely, SMN expression increases Bcl-xL protein levels by approximately 6-fold in SH-SY5Y cells, and approximately 2.5-fold in the brains of transgenic mice over-expressing SMN (PrP-SMN). Moreover, Sam68 protein levels were markedly reduced following SMN and Bcl-xL expression in SH-SY5Y cells, suggesting a feedback mechanism co-regulating levels of both proteins. We also found that exogenous SMN expression increased full-length SMN transcripts, possibly by promoting exon 7 inclusion. Finally, co-expression of SMN and Bcl-xL produced an additive anti-apoptotic effect following PI3-kinase inhibition in SH-SY5Y cells. Our findings implicate Bcl-xL as another potential target in SMA therapeutics, and indicate that therapeutic increases in SMN may arise from modest increases in total SMN. |
