Adenylosuccinate lyase (ADSL) functions in de novo purine synthesis (DNPS) and the purine nucleotide cycle. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal serum purine nucleotide levels but exhibit accumulation of dephosphorylated ADSL substrates, S-Ado, and SAICAr, the latter being implicated in neurotoxic effects through unknown mechanisms. We examined the phenotypic effects of ADSL depletion in human cells and their relation to phenotypic outcomes. Using specific interventions to compensate for reduced purine levels or modulate SAICAr accumulation, we found that diminished AMP levels resulted in increased DNA damage signaling and cell cycle delays, while primary ciliogenesis was impaired specifically by loss of ADSL or administration of SAICAr. ADSL-deficient chicken and zebrafish embryos displayed impaired neurogenesis and microcephaly. Neuroprogenitor attrition in zebrafish embryos was rescued by pharmacological inhibition of DNPS, but not increased nucleotide concentration. Zebrafish also displayed phenotypes commonly linked to ciliopathies. Our results suggest that both reduced purine levels and impaired DNPS contribute to neurodevelopmental pathology in ADSLD and that defective ciliogenesis may influence the ADSLD phenotypic spectrum.

• Keywords
• ADSL, ADSLD, DNA damage, SAICAR, cell biology, chicken, cilia, developmental biology, human, microcephaly, zebrafish,
• MeSH
• Adenylosuccinate Lyase deficiency   metabolism   MeSH
• Aminoimidazole Carboxamide analogs & derivatives   metabolism   MeSH
• Autistic Disorder metabolism   MeSH
• Cell Line MeSH
• Cell Cycle MeSH
• Ciliopathies metabolism   MeSH
• Zebrafish metabolism   MeSH
• Phenotype MeSH
• Phosphoproteins metabolism   MeSH
• Chickens metabolism   MeSH
• Humans MeSH
• Microcephaly metabolism   MeSH
• Neurogenesis * MeSH
• Autism Spectrum Disorder metabolism   MeSH
• Purine-Pyrimidine Metabolism, Inborn Errors metabolism   MeSH
• DNA Damage MeSH
• Microtubule-Associated Proteins metabolism   MeSH
• Cell Cycle Proteins metabolism   MeSH
• Purines metabolism   MeSH
• Ribonucleotides metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• Adenylosuccinate Lyase MeSH
• Aminoimidazole Carboxamide MeSH
• CCP110 protein, human MeSH Browser
• Phosphoproteins MeSH
• Microtubule-Associated Proteins MeSH
• Cell Cycle Proteins MeSH
• purine MeSH Browser
• Purines MeSH
• Ribonucleotides MeSH
• SAICAR MeSH Browser