Human Molecular Genetics Advance Access originally published online on July 29, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 19 2481-2489
DOI: 10.1093/hmg/ddg256
© 2003 Oxford University Press
Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy
1Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, 53111 Bonn, Germany, 2Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931 Cologne, Germany, 3Institute of Neuropathology, University Erlangen-Nuremberg, Krankenhausstrasse 8-10, 91054 Erlangen, Germany and 4Department of Neurosurgery, University Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany
Received May 8, 2003; Accepted July 25, 2003
Proximal spinal muscular atrophy (SMA) is a common neuromuscular disorder causing infant death in half of all patients. Homozygous absence of the survival motor neuron gene (SMN1) is the primary cause of SMA, while SMA severity is mainly determined by the number of SMN2 copies. One SMN2 copy produces only about 10% of full-length protein identical to SMN1, whereas the majority of SMN2 transcripts is aberrantly spliced due to a silent mutation within an exonic splicing enhancer in exon 7. However, correct splicing can be restored by over-expression of the SR-like splicing factor Htra2-ß1. We show that in fibroblast cultures derived from SMA patients treated with therapeutic doses (0.5–500 µM) of valproic acid (VPA), the level of full-length SMN2 mRNA/protein increased 2- to 4-fold. Importantly, this up-regulation of SMN could be most likely attributed to increased levels of Htra2-ß1 which facilitates the correct splicing of SMN2 RNA as well as to an SMN gene transcription activation. Especially at low VPA concentrations, the restored SMN level depended on the number of SMN2 copies. Moreover, VPA was able to increase SMN protein levels through transcription activation in organotypic hippocampal brain slices from rats. Finally, VPA also increased the expression of further SR proteins, which may have important implications for other disorders affected by alternative splicing. Since VPA is a drug highly successfully used in long-term epilepsy therapy, our findings open the exciting perspective for a first causal therapy of an inherited disease by elevating the SMN2 transcription level and restoring its correct splicing.
* To whom correspondence should be addressed at: Institute of Human Genetics, Wilhelmstrasse 31, 53111 Bonn, Germany. Tel: +49 2282872344; Fax: +49 2282872380; Email: bwirth{at}uni-bonn.de
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