Pathway specific effects of ADSL deficiency on neurodevelopment
- Institute for Research in Biomedicine, Spain
- University of Tubingen, Germany
- Instituto de Biología Molecular de Barcelona, Spain
- Charles University, Czech Republic
- National Cancer Institute, United States
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Spain
- University of Barcelona, Spain
- University of Tübingen, Germany
Abstract
Adenylosuccinate Lyase (ADSL) functions in de novo purine biosynthesis (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.
Data availability
Most data generated or analysed during this study are included in the manuscript and supporting source data files. Additional source data is available via Figshare, https://doi.org/10.25452/figshare.plus.c.5793614
Article and author information
Author details
Cedric Boeckx Prof
Martin D Burkhalter
Funding
H2020 Marie Skłodowska-Curie Actions (754510)
- Ilaria Dutto
Ministerio de Ciencia, Innovación y Universidades (PGC2018-099562-B-I00)
- Jens Lüders
Ministerio de Ciencia, Innovación y Universidades (PGC2018-095616-B-I00)
- Travis H Stracker
Deutsche Forschungsgemeinschaft (DFG PH144/4-1)
- Melanie Philipp
Deutsche Forschungsgemeinschaft (PH144/6-1)
- Melanie Philipp
Agència de Gestió d'Ajuts Universitaris i de Recerca (2017 SGR)
- Jens Lüders
- Travis H Stracker
Charles University (PROGRES Q26/LF1)
- Olga Souckova
- Václava Škopová
- Marie Zikánová
Ministry of Science, Innovation and Universities (BFU2017-83562-P)
- Sebastian Pons
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Pathway specific effects of ADSL deficiency on neurodevelopment
eLife 11:e70518.
https://doi.org/10.7554/eLife.70518
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