Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University of Tübingen, Tübingen, Germany; Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
Department of Cell Biology, Instituto de Biología Molecular de Barcelona, Barcelona, Spain
Olga Souckova
Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Václava Škopová
Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Jordann A Smak
National Cancer Institute, Center for Cancer Research, Radiation Oncology Branch, Bethesda, United States
Alexandra Junza
Universitat Rovira i Virgili, Department of Electronic Engineering, IISPV, Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
Oscar Yanes
Universitat Rovira i Virgili, Department of Electronic Engineering, IISPV, Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
ICREA, Barcelona, Spain; Institute of Complex Systems (UBICS), Universitat de Barcelona, Barcelona, Spain; Section of General Linguistics, Universitat de Barcelona, Barcelona, Spain
Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University of Tübingen, Tübingen, Germany
Marie Zikánová
Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Sebastian Pons
Department of Cell Biology, Instituto de Biología Molecular de Barcelona, Barcelona, Spain
Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University of Tübingen, Tübingen, Germany; Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain; National Cancer Institute, Center for Cancer Research, Radiation Oncology Branch, Bethesda, United States
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.
