Exploring the Causes of Muscle Dysfunction Associated with Adenylosuccinate Lyase Deficiency in the Model Organism Caenorhabditis elegans
Open Access
Author:
Jan, Judy
Area of Honors:
Biochemistry and Molecular Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
Wendy Hanna-Rose, Thesis Supervisor David Scott Gilmour, Thesis Honors Advisor
Keywords:
C. elegans Muscle Function Adenylosuccinate Lyase Deficiency Purine Metabolism
Abstract:
Adenylosuccinate Lyase Deficiency (ASLD) is caused by a mutation in a gene encoding for the adenylosuccinate lyase enzyme, which functions twice in the purine metabolic pathway, converting metabolites succinylaminoimidazole carboxamide ribotide (SAICAR) to 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and succinyladenosine monophosphate (S-AMP) to adenosine monophosphate (AMP). Elevated levels of succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado)—the dephosphorylated forms of SAICAR and S-AMP, respectively—in the body fluids of patients with ASLD have been observed. Previous research studying ASLD using the model organism C. elegans has looked at how muscle function is affected by decreased or eliminated adsl-1 expression; however, the cause of the changes in muscle function remains in contention. In this study, I further the research begun by the Hanna-Rose lab regarding the role that increased levels of SAICAR play in worms with reduced expression of adsl-1. I supplement adsl-1(RNAi) knockdown worms with water-soluble lometrexol, a drug inhibiting the de novo purine biosynthesis pathway upstream of where the adenylosuccinate lyase enzyme functions. I demonstrate that supplementation with lometrexol fully restores muscle function in adsl-1(RNAi) animals, suggesting that inhibition of the de novo purine biosynthesis pathway does improve muscle function in animals that have reduced adsl-1 expression. I also perform a metabolomics analysis to explore if there are any differences in mitochondrial function in worms with decreased adsl-1 expression to further the research on the additional possible contributing factors of muscle dysfunction in ASLD.
