Spinal muscular atrophy (SMA) is a neurodegenerative disease that results in the loss of motor neurons, muscle atrophy, paralysis, and infant mortality. The causative gene of SMA is SMN1, which encodes a survival motor neuron protein and is implicated in the regulation of splicing. Our project seeks to establish and characterize a new, promising link between SMA and high-glucose diet in Caenorhabditis elegans. C. elegans is an excellent model to study SMA, as the smn-1 gene is nearly 80% identical in worms and humans, and it is also a good model for to study the response to high-glucose diet due to the high level of conservation with the human insulin-signaling pathway.
Mutations in the C. elegans insulin receptor (daf-2) can lead to entry into an alternative larval stage called dauer. Previous studies have demonstrated that a high-glucose diet suppresses this effect due to the up-regulation of insulin signaling. We conducted a series of RNAi screens to identify regulators that are important for the insulin signaling response specifically on a high-glucose diet. We have identified 44 candidate genes. Interestingly, two of the most promising candidates are smn-1 and nekl-3, the latter of which has been identified as a modifier of smn-1. This identifies a potential link between SMA, high-glucose diet, and insulin signaling.
We have completed dauer assays to verify and quantify the insulin specificity and glucose specificity of these 44 candidate genes. ~30 other genes have been identified as smn-1 genetic interactors, and we have tested whether other members of this “SMA Network” are also involved in regulating insulin signaling. We find that the SMA Network genes are enriched for this response: ~25% are also required for the high-glucose diet suppression of dauer formation. SMA Network genes also seem to play a role in regulating other insulin-signaling phenotypes, including lifespan and stress resistance.