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Multiple effects of curcumin on promoting expression of the exon 7-containing SMN2 transcript.

ABSTRACT: Survival of motor neuron 2 (SMN2) is a modifier gene for spinal muscular atrophy (SMA), a neurodegenerative disease caused by insufficient SMN protein mostly due to SMN1 defect. SMN2 is nearly identical to SMN1 but unfortunately only able to produce a small amount of SMN protein due to exon 7 skipping. The exon 7-containing SMN2 transcript (SMN2_E7+) can be increased by a dietary compound, curcumin, but the involved molecular changes are not clear. Here we have found that in fibroblast cells of a SMA type II patient, curcumin enhanced the inclusion of SMN2 exon 7. Examination of the potential splicing factors showed that curcumin specifically increased the protein and transcript levels of SRSF1. The increased SRSF1 protein was mainly nuclear and hyperphosphorylated. Interestingly, the curcumin effects on the SMN2 and SRSF1 transcripts were inhibited by a protein deacetylase inhibitor, trichostatin A. Moreover, in support of its role in the SMN2 splicing, knocking down SRSF1 reduced the inclusion of SMN2 exon 7. Thus, curcumin appears to have multiple effects on the SMN2 transcript and its splicing regulators, including the change of alternative splicing and transcript/protein level as well as phosphorylation. Protein deacetylases and phosphatases are likely involved in these effects. Interestingly, the effects all seem to favor production of the SMN2_E7+ transcript in SMA patient cells.

SUBMITTER: Feng D

PROVIDER: S-EPMC4575656 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Multiple effects of curcumin on promoting expression of the exon 7-containing SMN2 transcript.

Feng Dairong D Cheng Yi Y Meng Yan Y Zou Liping L Huang Shangzhi S Xie Jiuyong J

Genes & nutrition 20150919 6

Survival of motor neuron 2 (SMN2) is a modifier gene for spinal muscular atrophy (SMA), a neurodegenerative disease caused by insufficient SMN protein mostly due to SMN1 defect. SMN2 is nearly identical to SMN1 but unfortunately only able to produce a small amount of SMN protein due to exon 7 skipping. The exon 7-containing SMN2 transcript (SMN2_E7+) can be increased by a dietary compound, curcumin, but the involved molecular changes are not clear. Here we have found that in fibroblast cells of ...[more]

PMID: 26386842

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Project description:Spinal muscular atrophy (SMA) is a rare hereditary neuromuscular disease with a high lethality rate in infants. Variants in the homologous genes survival of motor neuron (SMN)1 and SMN2 have been reported to be SMA pathogenic factors. Previous studies showed that a high inclusion rate of SMN2 exon 7 increased SMN expression, which in turn reduced the severity of SMA. The inclusion rate of SMN2 exon 7 was higher in neural tissues than in non-neural tissues. Neuro-oncological ventral antigen (NOVA) is a splicing factor that is specifically and highly expressed in neurons. It plays a key role in nervous system development and in the induction of nervous system diseases. However, it remains unclear whether this splicing factor affects SMA. In this study, we analyzed the inclusion of SMN2 exon 7 in different tissues in a mouse model of SMA (genotype smn-/-SMN22tg/0) and littermate controls (genotype smn+/-SMN22tg/0). We found that inclusion level of SMN2 exon 7 was high in the brain and spinal cord tissue, and that NOVA1 was also highly expressed in nervous system tissues. In addition, SMN2 exon 7 and NOVA1 were expressed synchronously in the central nervous system. We further investigated the effects of NOVA1 on disease and found that the number of neurons in the anterior horn of spinal cord decreased in the mouse model of SMA during postnatal days 1-7, and that NOVA1 expression levels in motor neurons decreased simultaneously as spinal muscular atrophy developed. We also found that in vitro expression of NOVA1 increased the inclusion of SMN2 exon 7 and expression of the SMN2 protein in the U87MG cell line, whereas the opposite was observed when NOVA1 was knocked down. Finally, point mutation and RNA pull-down showed that the UCAC motif in SMN2 exon 7 plays a critical role in NOVA1 binding and promoting the inclusion of exon 7. Moreover, CA was more essential for the inclusion of exon 7 than the order of Y residues in the motif. Collectively, these findings indicate that NOVA1 interacts with the UCAC motif in exon 7 of SMN2, thereby enhancing inclusion of exon 7 in SMN2, which in turn increases expression of the SMN protein.

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Multiple effects of curcumin on promoting expression of the exon 7-containing SMN2 transcript.

Publications

Multiple effects of curcumin on promoting expression of the exon 7-containing SMN2 transcript.

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