title: Systems biology investigation of cAMP modulation to increase SMN levels for the treatment of spinal muscular atrophy.
abstract: 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.
authors.affiliation: Center for Applied Clinical Genomics, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America; Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, Delaware, United States of America.
authors.forename: Sean G
authors.initials: SG
authors.lastname: Mack
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, Delaware, United States of America.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cook
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, Delaware, United States of America.
authors.forename: Prasad
authors.initials: P
authors.lastname: Dhurjati
authors.affiliation: Center for Applied Clinical Genomics, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America; Center for Pediatric Research, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America; Department of Biological Sciences, University of Delaware, Newark, Delaware, United States of America; Department of Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Matthew E R
authors.initials: ME
authors.lastname: Butchbach
mesh_terms: D000420:Albuterol / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D004837:Epinephrine / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020218:Response Elements / Q000235:genetics*; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics* / Q000627:therapeutic use*; D049490:Systems Biology / Q000379:methods
chemical_list: D055540:Survival of Motor Neuron 2 Protein; D005576:Colforsin; D003994:Bucladesine; D000242:Cyclic AMP; C490245:GEM protein, human; D020559:Monomeric GTP-Binding Proteins; D020889:Rolipram; D000420:Albuterol; D004837:Epinephrine