Abstract:
:The loss of survival motor neuron-1 (SMN1) is responsible for the development of the neurodegenerative disorder spinal muscular atrophy (SMA). A nearly identical copy of SMN1 is present on the same chromosomal region called SMN2. While SMN2 encodes a normal SMN protein, the majority of SMN2-derived transcripts are alternatively spliced, resulting in a truncated protein that lacks the 16 amino acids encoded by SMN exon 7. Numerous studies have shown that the SMN2-derived protein product, called SMNDelta7, is unstable and dysfunctional. Therefore, identifying molecules that stimulate full-length SMN expression from the SMN2 gene could lead to the development of effective therapies for a broad range of SMA patient populations. Polyphenol compounds have been shown to provide benefit in varied genetic disease contexts. For example, epigallocatechin galate (EGCG) was found to correct aberrant alternative mRNA splicing in familiar dysautonomia (FD). A series of polyphenols were screened and a subset was shown to increase full-length SMN expression from SMN2. Curcumin, EGCG, and resveratrol increased exon 7 inclusion of SMN2 transcripts in transient reporter assays. In SMA patient fibroblasts, these compounds stimulated the production of full-length SMN RNA and protein as well as the formation of SMN-containing nuclear gems. Collectively, these compounds elevated total SMN concentrations in SMA patient fibroblasts, potentially through the modulation of SMN2 exon 7 alternative splicing.
journal_name
Hum Genetjournal_title
Human geneticsauthors
Sakla MS,Lorson CLdoi
10.1007/s00439-007-0441-0subject
Has Abstractpub_date
2008-01-01 00:00:00pages
635-43issue
6eissn
0340-6717issn
1432-1203journal_volume
122pub_type
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