Analysis of the influence of histone deacetylase inhibitors on the SMN2 histone code and the pathogenesis of spinal muscular atrophy
Final Report Abstract
During the past funding period we were highly successful in the identification and characterization of several HDACi upregulating SMN in vitro and in vivo: VPA, SAHA, LBH589 and JNJ26481585. We showed that SMN upregulation is the result of different mechanism: activation of transcription, regulation of splicing, reduced ubiquitinylation of SMN as well as DNA methylation. By applying SAHA in vivo in two SMA mouse models, we showed that this HDACi significantly improves the SMA phenotype and restores the muscle fiber size, the number of motor neurons, the NMJ size and it connectivity to almost normal level. However another HDACi JNJ26481585 turned out to be less efficient mainly due to the dramatic development of the very severely affected SMA mice. These mice presented major organ impairment including heart, intestine and lung aside from muscle weakness and atrophy. In the context of the variable response to VPA, we generated IPS cells from fibroblasts of SMA patients. Having these versatile cells, we showed for the first time that there is a highly concordant response to VPA between blood, fibroblasts and neurons in SMA patients. Thus, skin biopsies followed by in vitro VPA treatment could be used as a preliminary triage for positive responders. VPA non-responsiveness is mediated by increased levels of CD36, which by a yet unknown mechanism prohibits the reach of effective VPA concentrations in the nucleus as well as in the cytoplasm. Therefore, decreased CD36 levels in fibroblasts might be considered as an indicative biomarker for a positive response to VPA.
Publications
- LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients nonresponsive to valproate. Hum Mol Genet, (2009),18(19):3645-3658
Garbes L, Riessland M, Hölker I, Heller R, Hauke J, Tränkle C, Coras R, I. Blümcke, Hahnen E, Wirth B
- Survival Motor Neuron Gene 2 Silencing by DNA Methylation Correlates with Spinal Muscular Atrophy Disease Severity and can be Bypassed by Histone Deacetylase Inhibition. Hum Mol Genet, (2009),18(2):304-317
Hauke J, Riessland M, Lunke S, Eyupoglu IY, Blumcke I, El-Osta A, Wirth B, Hahnen E
- SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy. Hum Mol Genet, (2010),19(8):1492- 1506
Riessland M, Ackermann B, Förster A, Jakubik M, Hauke J, Garbes L, Fritzsche I, Mende Y, Blümcke I, Hahnen E, Wirth B
