Induction of full-length survival motor neuron by polyphenol botanical compounds

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.

Epigallocatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production

“…These results suggest that EGCG might influence pre-mRNA splicing of gp130 toward formation of mRNA transcripts that synthesize sgp130 and warrants further testing. This notion is further supported by recent studies in which EGCG was found to inhibit the loss of survival motor neuron-1 protein and also to produce a full-length functional protein by correcting an aberrant alternative mRNA splicing in the cells from familial dysautonomia patients (39,40). However, our study demonstrates that EGCG can induce alternative mRNA splicing to produce a truncated form (i.e., sgp130) with potent antagonistic activity.…”

Protein Kinase C δ (PKCδ) Splice Variants Modulate Apoptosis Pathway in 3T3L1 Cells during Adipogenesis

“…Several studies have shown its role in inhibiting adipose cell proliferation, lipid accumulation, and stimulation of apoptosis and lipolysis in mature adipocytes. Further, resveratrol is shown to modulate alternative splicing of pre-mRNA (30). However, its mechanisms of action and target proteins in apoptotic pathway during adipogenesis was not determined.…”

Alteration of splice site selection in the LMNA gene and inhibition of progerin production via AMPK activation

“…Although activation of AMPK by metformin, resveratrol, and berberine have been well documented, several naturally occurring AMPK-activating compounds have also been shown to correct aberrant alternative splicing in various disease states, including EGCG (corrected aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia) and curcumin (stimulated full-length production of SMN RNA and protein in patient fibroblasts, increasing the inclusion of exon 7 in SMN2 transcripts) [110][111][112][113]. Additionally, histone deacetylases (HDACs) have also been shown to modulate alternative splicing by influencing splice site selection [114].…”