Determination of the ADSL deficiency-directed perturbation and mechanism
Research Poster Health & Life Sciences 2025 Graduate ExhibitionPresentation by Sabrina Sony
Exhibition Number 64
Abstract
Adenylosuccinate lyase (ADSL) is a crucial enzyme in the de novo purine biosynthesis pathway. ADSL deficiency is a rare disorder causing muscle dysfunction and behavioral abnormalities including autistic-like symptoms. The deficiency leads to substrate SAICAR accumulation and purine homeostasis disruption. Each effect is thought to contribute to generating the phenotypes but the mechanisms linking metabolic effects to behavioral symptoms are unknown. We use C. elegans to investigate the neurobehavioral functions of the adsl-1 gene. Animals with reduced adsl-1 gene function exhibit slow, uncoordinated movement and altered learning phenotype. We assessed phenotypes after pharmacologically manipulating SAICAR levels to determine the effect of distinct metabolic changes on phenotypes. Our results indicated that increased SAICAR levels contribute to learning and head oscillation phenotypes. Analysis of metabolites of wild type and adsl-1 animals revealed that tyrosine metabolism is perturbed when adsl-1 gene function is reduced, which led us to discover that the learning difference results from the deficiency of the tyrosine-derived biogenic amine tyramine. Loss of tdc-1, which synthesizes tyramine, causes an adsl-1-like learning difference, and the learning phenotype of both adsl-1 and tdc-1 is ameliorated with tyramine supplementation. Additionally, adsl-1 exhibits the same head oscillation phenotype as tdc-1 mutants, supporting tyramine reduction. We also assessed phenotypes after supplementing animals with purines. We found that adenosine partially restores learning but not head oscillation, revealing its direct role in gustatory plasticity rather than tyrosine metabolism. A deeper understanding of these pathways could provide insights into therapeutic approaches for ASLD and related disorders.
Importance
Modeling metabolic disorders using animal models is vital in understanding disorders in hopes to further investigate the molecular mechanisms and help elucidate possible treatments in the future. The molecular mechanisms that link perturbations of purine biosynthesis to behavioral symptoms and neurological disease are unknown. Another justification for this study is that therapies for ASLD are inadequate and mostly rely on epilepsy treatment. Hence, there is a critical need to determine how behavioral outcomes are influenced by tyrosine pathway linked through unknown ways to purine biosynthesis. Understanding this mystery can help us move closer to discovering a potential therapeutic approach.
DEI Statement
ASLD is a rare and underrepresented disorder, leading to delayed diagnoses and limited treatment options. Advancing ASLD research is a matter of health equity, ensuring that all individuals benefit from scientific progress regardless of their background. By fostering inclusive collaboration and amplifying diverse voices in biomedical research, we can drive innovative solutions and advocate for neglected diseases. Our commitment to studying ASLD contributes to a more just healthcare system, where no disease is overlooked, and every patient has hope for effective treatment.