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Spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an autosomal recessive disorder caused by the loss of  SMN1 (survival motor neuron 1) , which encodes the protein SMN. The loss of  SMN1  causes a deficiency in SMN protein levels leading to motor neuron cell death in the anterior horn of the spinal cord.  SMN2 , however, can also produce some functional SMN to partially compensate for loss of  SMN1  in SMA suggesting increasing transcription of  SMN2  as a potential therapy to treat patients with SMA. A cAMP response element was identified on the  SMN2  promoter, implicating cAMP activation as a step in the transcription of  SMN2 . Therefore, we investigated the effects of modulating the cAMP signaling cascade on SMN production  in vitro  and  in silico . SMA patient fibroblasts were treated with the cAMP signaling modulators rolipram, salbutamol, dbcAMP, epinephrine and forskolin. All of the modulators tested were able to increase gem formation, a marker for SMN protein in the nucleus, in a dose-dependent manner. We then derived two possible mathematical models simulating the regulation of  SMN2  expression by cAMP signaling. Both models fit well with our experimental data.  In silico  treatment of SMA fibroblasts simultaneously with two different cAMP modulators resulted in an additive increase in gem formation. This study shows how a systems biology approach can be used to develop potential therapeutic targets for treating SMA.

Systems Biology Investigation of cAMP Modulation to Increase SMN Levels for the Treatment of Spinal Muscular Atrophy