Comparative Effectiveness of Novel Therapeutics on Treating Neuromuscular Symptoms Associated with Adenylosuccinate Lyase Deficiency

open_access
Open Access
Author:
Gelman, Ryan
Area of Honors:
Biochemistry and Molecular Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
Wendy Hanna-Rose, Thesis Supervisor
Teh-Hui Kao, Thesis Honors Advisor
Keywords:
C. elegans
Purine Metabolism
model organism
adenylosuccinate lyase deficiency
Abstract:
Mutations in enzymes involved in purine metabolism can lead to severe metabolic disorders characterized by diverse neurological, neuromuscular, and developmental dysfunctions. Adenylosuccinate Lyase Deficiency (ADSL Deficiency) is an inborn error in purine metabolism caused by deficient levels of functional adenylosuccinate lyase (ADSL). ADSL is an enzyme used twice in the de novo purine biosynthesis pathway, and its absence leads to a buildup of toxic metabolic intermediates. ADSL deficiency is an ultra-rare disease in humans characterized by neurological and developmental impairments: seizures, hypotonia, psychomotor retardation, developmental delay, autistic-like behaviors, and, in extreme cases, even death. Despite its broad range of dangerous symptoms, ADSL deficiency is a disease that currently has no cure and lacks many treatment options. I investigated the therapeutic potential of two compounds, malathion and uracil 1-β-D-arabinofuranoside (Ara-U), in treating ADSL deficiency using Caenorhabditis elegans as a model for the disease. Using C. elegans deficient in the adsl-1 gene either through RNAi knockdown or genetic knockout, I examined whether supplementation with these compounds would improve the morphological and locomotive phenotypes associated with impaired purine metabolism. Malathion proved ineffective in improving the locomotive behavior of adsl-1 deficient C. elegans. Ara-U supplementation produced modest improvement in the swimming behavior of the knockout animals, producing a significant improvement in the thrashing rate of the animals. These findings are not conclusive of Ara-U’s efficacy as a treatment for ADSL deficiency, but serve as strong preliminary insight into its potential as a therapeutic of ADSL deficiency modeled in C. elegans.