Abstract:
:Spinal muscular atrophy (SMA) is a motor neuron disease caused by loss of function mutations in the Survival Motor Neuron 1 (SMN1) gene and reduced expression of the SMN protein, leading to spinal motor neuron death, muscle weakness and atrophy. Although humans harbour the highly homologous SMN2 gene, its defective splicing regulation yields a truncated and unstable SMN protein. The first therapy for SMA was recently approved by the Food and Drug Administration and consists of an antisense oligonucleotide (Nusinersen) rendering SMN2 functional and thus improving patients' motor activity and quality of life. Nevertheless, not all patients equally respond to this therapy and the long-term tolerability and safety of Nusinersen are still unknown. Herein, in vivo splicing assays indicated that the HDAC inhibitor LBH589 is particularly efficient in rescuing the SMN2 splicing defect in SMA fibroblasts and SMA type-I mice-derived neural stem cells. Western blot analyses showed that LBH589 also causes a significant increase in SMN protein expression in SMA cells. Moreover chromatin immunoprecipitation analyses revealed that LBH589 treatment induces widespread H4 acetylation of the entire SMN2 locus and selectively favors the inclusion of the disease-linked exon 7 in SMN2 mature mRNA. The combined treatment of SMA cells with sub-optimal doses of LBH589 and of an antisense oligonucleotide that mimic Nusinersen (ASO_ISSN1) elicits additive effects on SMN2 splicing and SMN protein expression. These findings suggest that HDAC inhibitors can potentiate the activity of Nusinersen and support the notion that 'SMN-plus' combinatorial therapeutic approaches might represent an enhanced opportunity in the scenario of SMA therapy.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Pagliarini V,Guerra M,Di Rosa V,Compagnucci C,Sette Cdoi
10.1111/jnc.14935subject
Has Abstractpub_date
2020-04-01 00:00:00pages
264-275issue
2eissn
0022-3042issn
1471-4159journal_volume
153pub_type
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pub_type: 杂志文章
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更新日期:2009-04-01 00:00:00
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pub_type: 杂志文章
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journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
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