Pathway-specific effects of ADSL deficiency on neurodevelopment

• DOI: 10.7554/elife.70518
• Publication Date: 2022-02-08T14:15:12Z
• Authors: Ilaria Dutto; Julian Gerhards; Antonio Herrera; Olga Souckova; Václava Škopová; Jordann A Smak; Alexandra Junza; Oscar Yanes; Cedric Boeckx; Martin D Burkhalter; Marie Zikánová; Sebastian Pons; Melanie Philipp; Jens Lüders; Travis H Stracker
• Keywords: Microcephaly

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