Justin Minnerly

Increased neuronal excitability causes seizures with debilitating symptoms. Effective and noninvasive treatments are limited
for easing symptoms, partially due to the complexity of the disorder and lack of knowledge of specific molecular faults. An
unexplored, novel target for seizure therapeutics is the cGMP/protein kinase G (PKG) pathway, which targets downstream
K+
channels, a mechanism similar to Retigabine, a recently FDA-approved antiepileptic drug. Our results demonstrate that
increased PKG activity decreased seizure duration in C. elegans utilizing a recently developed electroconvulsive seizure
assay. While the fly is a well-established seizure model, C. elegans are an ideal yet unexploited model which easily uptakes
drugs and can be utilized for high-throughput screens. In this study, we show that treating the worms with either a potassium
channel opener, Retigabine or published pharmaceuticals that increase PKG activity, significantly reduces seizure recovery
times. Our results suggest that PKG signaling modulates downstream K+
channel conductance to control seizure recovery
time in C. elegans. Hence, we provide powerful evidence, suggesting that pharmacological manipulation of the PKG signaling
cascade may control seizure duration across phyla.

Restriction of dietary food without malnutrition robustly extends lifespan in more than
twenty species. It was also reported that fruit flies (Drosophila melanogaster) deficient in
olfactory function live longer and that the longevity induced by food restriction is partially
due to decreased olfaction. These observations suggest food assimilation through the gastrointestinal
tract and food smell detected by olfactory neurons influence lifespan. The
insulin growth factor signaling pathway is regulated by nutrient levels and has been shown
to mediate the lifespan extension conferred by food restriction and defective gustatory neurons
in the nematode Caenorhabditis elegans. However, the mechanism remains unclear.
Autophagy is a lysosomal degradation pathway and is sensitive to nutrient availability. We
found autophagy activity in the intestine and food sensory neurons acts in parallel to mediate
food restriction and insulin signaling regulated lifespan extension in Caenorhabditis elegans.
Moreover, intestinal and neuronal autophagy converge on unidentified neurons to
control the secretion of neuropeptides that regulate lifespan. These data suggest autophagy is an essential component in a neuroendocrine pathway that coordinates how environmental
food cues detected by sensory neurons and food nutrients assimilated by the intestine
influence lifespan. These findings may contribute to understanding the aging process in
mammals.

Salmonella typhimurium infects both intestinal epithelial cells and macrophages. Autophagy is a lysosomal
degradation pathway that is present in all eukaryotes. Autophagy has been reported to limit the
Salmonella replication in Caenorhabditis elegans and in mammals. However, it is unknown whether intestinal
autophagy activity plays a role in host defense against Salmonella infection in C. elegans. In this
study, we inhibited the autophagy gene bec-1 in different C. elegans tissues and examined the survival
of these animals following Salmonella infection. Here we show that inhibition of the bec-1 gene in the
intestine but not in other tissues confers susceptibility to Salmonella infection, which is consistent with
recent studies in mice showing that autophagy is involved in clearance of Salmonella in the intestinal epithelial
cells. Therefore, the intestinal autophagy activity is essential for host defense against Salmonella
infection from C. elegans to mice, perhaps also in humans.