Adenylosuccinate lyase deficiency (ASLD) is a rare inborn error of purine metabolism. The enzyme that causes the disease, adenylosuccinate lyase (ADSL), catalyzes two non-sequential steps in the de novo purine pathway. Patients with ASLD have decreased ADSL activity, leading to neurological and muscular dysfunction. Clinical presentations include ataxia, motor deficits, autistic-like behavior, and seizures. Currently, no therapeutic treatment is available other than seizure prevention. ADSL is a conserved gene and is called
adsl-1 in C. elegans. We have used RNAi and a deletion allele to investigate learning and behavioral phenotypes associated with
adsl-1. We have used both associative and non-associative learning to explore the learning aspects of ASLD in
adsl-1 animals. In an associative learning assay, both naive control and
adsl-1(RNAi) animals are strongly attracted to sodium chloride, indicating no defect in chemotaxis in the mutant. However, when sodium chloride is paired briefly with food depravation, control animals become indifferent to the salt, whereas
adsl-1(RNAi) animals hyper-respond to the cue pairing and become repelled. Thus, associative learning occurs, but the outcome is altered in
adsl-1(RNAi) animals. We used mechanosensory habituation assays to examine non-associative learning and found that a proportion (40%) of
adsl-1(RNAi) animals do not respond to tap, indicating a potential sensory defect. The proportion of
adsl-1(RNAi) animals that do respond to tap habituate more quickly than control animals, again suggesting an altered and hyper-focused learning capacity. While we detected an incompletely penetrant defect in tap response,
adsl-1(RNAi) animals respond normally to nose touch and gentle touch sensory assays. Treatment with a GART inhibitor ameliorates the
adsl-1 (RNAi) learning phenotype. SAICAR substrate has been proposed to be toxic, and may cause the learning phenotype in
adsl-1. Via targeted LC/MS analysis we found that
adsl-1(RNAi) animals have increased levels of SAICAR relative to control animals where SAICAR levels are undetectable, consistent with a role for SAICAR in determining phenotypic outcome.