The Role of Sphingomyelin Synthase on the Healthspan of Organisms Via Modulating Neurotransmission

Abstract

Individuals are living longer due to medical interventions; however, simply increasing lifespan without proportionally increasing healthspan will result in longer periods of decrepitude. Healthspan is defined as the length of time before the onset of morbidity. One metric of healthspan that decreases as organisms age is neuronal function. To determine signaling molecules that may mediate healthy neuronal function, we examined neuromuscular function in the model organism C. elegans. In particular, we systematically analyzed a class of lipids called sphingolipids. Sphingolipids mediate for a variety of cellular signaling functions such as cell proliferation and apoptosis, but also involved in neurotransmission by interacting with neurotransmitter receptors and promoting neurotransmitter release. Sphingolipids are interconverted by metabolic enzymes that balance the levels of lipids within cells. We examined changes in neuromuscular function with age of C. elegans knockouts in several sphingolipid converting enzymes, including sphingomyelin (SM) synthases (sms‐1, sms‐3), ceramidase (asah‐2) and ceramide synthase double mutant (lagr‐1, hyl‐1). Sphingomyelin synthase converts ceramide to sphingomyelin. Additionally, ceramide synthase converts sphingosine to ceramide. We experimented with these mutants because both sphingomyelin and ceramide play important roles in the production of neurotransmitter receptors. To examine neuromuscular changes with age, we examined worm trashing behavior in 5, 10, and 15 day old worms. We found that mutants lacking sms‐1/SM synthase had decreased thrashing in comparison to wildtype worms at all ages. As stated, SM affects neurotransmission and development, but it is still unclear at which age window SM levels will have the most prominent effect. Therefore, we aim to further observe the role of SM during development and adulthood. We will expose wildtype and mutant worms with a pharmacological agent, D609 which inhibits sphingomyelin synthases. We will treat D609 specifically during development or adult time frames. Lastly, we wanted to further investigate this phenomena by investigating changes in aspects of synaptic vesicle cycling such as exocytosis and endocytosis. To do this, we will examine changes in the synapses of the neuromuscular junction (NMJ) by analyzing changes in GFP‐tagged synaptic markers with age and when exposed to the D609 drug treatments. These results will help identify how sphingomyelin processing enzymes might affect neurotransmission that may have a cascading effect on health span in aging animals.Support or Funding InformationASBMBThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.