Spinal muscular atrophy: identification of pathways critical for SMN function

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder primarily affecting children. It is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein. Studies in people with SMA and murine SMA models have shown that increased SMN protein levels are associated with milder forms of the disease. Identifying the pathways and drug compounds that increase SMN levels would suggest a direct therapeutic strategy for treating SMA patients. However, another complementary approach could be considered: the identification of pathways that act independently of SMN function and can help correct levels of SMN.

Manipulation of these pathways can increase the effective activity of the SMN protein already present in patients with SMA. I have recently identified conserved genetic pathways that affect SMN neuromuscular function on a previously defined invertebrate Caenorhabditis elegans (C. elegans) model of SMA. In this study I will use the genetic tools of C. elegans to dissect the mechanism(s) by which the cross-species pathways control SMN synaptic function.

The ultimate goal is to identify novel therapeutic avenues that will attenuate SMA in mammalian models.