Using Systems Biology and Mathematical Modeling Approaches in the Discovery of Therapeutic Targets for Spinal Muscular Atrophy
Systems biology uses a combination of experimental and mathematical approaches to investigate the complex and dynamic interactions with a given system or biological process. Systems biology integrates genetics, signal transduction, biochemistry and cell biology with mathematical modeling. It can be used to identify novel pathways implicated in diseases as well as to understand the mechanisms by which a specific gene is regulated. This review describes the development of mathematical models for the regulation of an endogenous modifier gene, SMN2, in spinal muscular atrophy—an early-onset motor neuron disease that is a leading genetic cause of infant mortality worldwide—by cAMP signaling. These mathematical models not only can aid in understanding how SMN2 expression is regulated but they can also be used to examine the best ways to manipulate cAMP signaling to maximally increase SMN2 expression. These models will lead to the development of therapeutic strategies for treating SMA. This systems biology approach can also be applied to other neurological diseases, particularly those in which a disease-causing gene or a modifier gene has been identified.
KeywordsSpinal muscular atrophy Drug discovery SMN2 Ordinary differential equations Gene expression Mathematical modeling
Cyclic nucleotide phosphodiesterase
CRE binding protein
Enzyme-linked immunosorbent assay
Exonic splicing enhancer
Full length SMN
G protein-coupled receptor
Insulin-like growth factor 1 receptor
Ordinary differential equation
Partial differential equation
cAMP-dependent protein kinase
Protein phosphatase 2A
Spinal muscular atrophy
Survival motor neuron 1
Survival motor neuron 2
SMN lacking exon 7
Single nucleotide variant
This work was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (P30GM114736) and by the Nemours Foundation.
Conflict of Interest
The author declares no conflict of interest.
- Branchu J, Biondi O, Chali F, Collin T, Leroy F, Mamchaoui K, et al. Shift from extracellular signal-related kinase to AKT/cAMP response element-binding protein pathway increases survival-motor-neuron expression in spinal-muscular-atrophy-like mice and patient cells. J Neurosci. 2013;33:4280–94.CrossRefGoogle Scholar
- Zhang Z, Keleman O, Van Santen MA, Yelton SM, Wendlandt AE, Sviripa VM, et al. Synthesis and characterization of pseudocantharidins, novel phosphatase modulators that promote the inclusion of exon 7 into the SMN (survival of motoneuron) pre-mRNA. J Biol Chem. 2011;286:10126–36.CrossRefGoogle Scholar