Adenylosuccinate synthetase deficiency and purine nucleotide cycle disruption impair neuromuscular function in...

The critical role of the purine nucleotide cycle (PNC) in human health is underscored by the fact that mutations in adenylosuccinate synthetase (ADSS) and adenylosuccinate lyase (ADSL), two of its three enzymes, are associated with severe inborn errors of purine metabolism. We use Caenorhabditis elegans to investigate the biological roles of the PNC and to characterize developmental and behavioral functions of ADSS and ADSL. Here we report that adss-1, which encodes ADSS in C. elegans, is required for fertility and locomotion. adss-1 loss-of-function mutants also have small body size, and their development is severely delayed. These phenotypes are shared with adsl-1, which encodes ADSL, suggesting that an intact PNC is required for C. elegans development. Interestingly, adss-1 and adsl-1 each have unique phenotypes not shared with the other. adss-1-specific phenotypes include excessive excitatory (or decreased inhibitory) synaptic transmission at the neuromuscular junction and impaired mechanosensation, suggesting an important function in the nervous system. We have also established a powerful model for further investigation of how ADSS activity impacts mobility, providing insight into the poorly understood molecular mechanisms driving phenotypic outcomes in ADSS1 deficiency.