DYSFUNCTION IN THE BIOSYNTHETIC NAD+ SALVAGE PATHWAY AND PURINE BIOSYNTHESIS PATHWAY ALTER NEUROLOGICAL FUNCTION IN CAENORHABDITIS ELEGANS
Open Access
Author:
Rohan, Laura Elizabeth
Area of Honors:
Biochemistry and Molecular Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
Dr. Wendy Hanna-Rose, Thesis Supervisor Dr. Teh-hui Kao, Thesis Honors Advisor
Keywords:
C. elegans Metabolism Neurological Purine Nicotinamide Model system
Abstract:
The proper function of specific metabolic pathways is often crucial in normal neuronal functioning. Using the model system Caenorhabditis elegans, I investigated the neurological effects of disrupting two metabolic processes: salvage biosynthesis of NAD+ and de novo purine biosynthesis.
Nicotinamide (NAM) build-up in C. elegans causes death in OLQ neurons, mediated by the OSM-9—OCR-4 TRPV channel. TRPV channels are important mediators of behavioral responses to a variety of exogenous and endogenous stimuli. I investigated another TRPV channel, an OSM-9—OCR-2 TRPV channel known to affect sensitivity to a nose touch response. As knockout of ocr-4 shows no effect on nose touch response, it is determined that OCR-4 plays no role in this sensory response mechanism. pnc-1 knockout mutants, which have increased NAM levels, are shown to exhibit a decreased responsiveness to the nose touch stimulus in more than one condition, indicating that NAM is an agonist for more TRPV channels besides the OSM-9—OCR-4 channel.
ADSL is a crucial enzyme in the purine biosynthesis pathway. When absent in humans, neurological phenotypes, such as seizures and epilepsy, are observed. To test the precise molecular cause of such phenotypes, a neurological phenotype model is necessary. I endeavored to utilize an assay testing gustatory plasticity, or associative learning ability, in the building of such a model. The primary results of this assay are promising, showing that adsl-1 mutant animals possess an increased ability to learn to avoid previously positive stimuli after a negative experience, as compared to wild-type worms.