期刊
NEUROSCIENCE LETTERS
卷 442, 期 1, 页码 54-58出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2008.06.059
关键词
spinal muscular atrophy (SMA); survival motor neuron (SMN); read-through
资金
- Clinical BioDectives Program [T90 DK070105]
- Phi Zeta-Pi Chapter Research
- FightSMA
- Muscular Dystrophy Association
- National Institutes of Health [R01 NS41584, R01 HD054413]
Spinal muscular atrophy (SMA) affects about 1 in every 6000 children born and is the leading genetic cause of infant death. SMA is a recessive disorder caused by the mutation or deletion of Survival Motor Neuron-1 (SMN1). SMN2, a nearly identical copy gene, has the potential to encode the same protein as SMN1 and is retained in all SMA patients. The majority of SMN2-derived transcripts are alternatively spliced and therefore encode a truncated isoform lacking exon 7 (SMN Delta 7). which is a defective protein because it is unstable, has a reduced ability to self-associate and is unable to efficiently function in SMN cellular activities. However, we have shown that the SMN C-terminus functions non-specifically, since heterologous sequences can compensate for the exon 7 sequence. Several classes of compounds identified in SMN-inducing high throughput screens have been proposed to function through a read-through mechanism; however, a functional analysis of the SMN Delta 7 read-through product has not been per-formed. In this report, the SMN Delta 7 read-through product is characterized and compared to the SMN Delta 7 protein. In a series of in vitro and cell based assays, SMN Delta 7 read-through product is shown to increase protein stability, promote neurite outgrowths in SMN deficient neurons, and significantly elevate SMN-dependent UsnRNP assembly in extracts from SMA patient fibroblasts. Collectively, these results demonstrate that SMN Delta 7 read-through product is more active than the SMN Delta 7 protein and suggest that SMA therapeutics that specifically induce SMN Delta 7 read-through may provide an alternative platform for drug discovery. (c) 2008 Elsevier Ireland Ltd. All rights reserved.
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