A Caenorhabditis elegans model of adenylosuccinate lyase deficiency reveals neuromuscular and reproductive phenotypes of distinct etiology

Abstract

Inborn errors of purine metabolism are rare syndromes with an array of complex phenotypes in humans. One such disorder, adenylosuccinate lyase deficiency (ASLD), is caused by a decrease in the activity of the bi-functional purine biosynthetic enzyme, adenylosuccinate lyase (ADSL). Mutations in human ADSL cause epilepsy, muscle ataxia, and autistic-like symptoms. Although the genetic basis of ASLD syndrome is known, the molecular mechanisms driving phenotypic outcome are not. Here, we characterize neuromuscular and reproductive phenotypes associated with a deficiency of adsl-1 in Caenorhabditis elegans. Characterization of the neuromuscular phenotype reveals a disruption of cholinergic transmission affecting muscular contraction. Using genetics, pharmacological supplementation, and metabolite measurements, we correlate phenotypes with distinct metabolic perturbations. The neuromuscular defect is associated with a toxic accumulation of a purine biosynthetic intermediate whereas the reproductive defect can be ameliorated by purine supplementation, indicating differing molecular mechanisms behind the phenotypes of ASLD. Because purine metabolism is highly conserved in metazoans, we suggest that similar separable metabolic perturbations result in the varied symptoms in the human disorder and that a dual-approach therapeutic strategy may be beneficial.