Biological networks and complexity in early-onset motor neuron diseases

Abstract

Motor neuron diseases (MNDs) are neuromuscular disorders where the spinal motor neurons–either the cell bodies themselves or their axons–are the primary cells affected. To date, there are 120 different genes that are lost or mutated in pediatric-onset MNDs. Most of these childhood-onset disorders, aside from spinal muscular atrophy (SMA), lack viable therapeutic options. Previous research on MNDs has focused on understanding the pathobiology of a single, specific gene mutation and targeting therapies to that pathobiology. This reductionist approach has yielded therapeutic options for a specific disorder, in this case SMA. Unfortunately, therapies specific for SMA have not been effective against other pediatric-onset MNDs. Pursuing the same approach for the other defined MNDs would require development of at least 120 independent treatments raising feasibility issues. We propose an alternative to this this type of reductionist approach by conceptualizing MNDs in a complex adaptive systems framework that will allow identification of common molecular and cellular pathways which form biological networks that are adversely affected in early-onset MNDs and thus MNDs with similar phenotypes despite diverse genotypes. This systems biology approach highlights the complexity and self-organization of the motor system as well as the ways in which it can be affected by these genetic disorders. Using this integrated approach to understand early-onset MNDs, we would be better poised to expand the therapeutic repertoire for multiple MNDs.