Pathway specific effects of ADSL deficiency on neurodevelopment

  1. Ilaria Dutto
  2. Julian Gerhards
  3. Antonio Herrera
  4. Olga Souckova
  5. Václava Škopová
  6. Jordann Smak
  7. Alexandra Junza
  8. Oscar Yanes
  9. Cedric Boeckx Prof
  10. Martin D Burkhalter
  11. Marie Zikánová
  12. Sebastian Pons
  13. Melanie Philipp
  14. Jens Lüders
  15. Travis H Stracker  Is a corresponding author
  1. Institute for Research in Biomedicine, Spain
  2. University of Tubingen, Germany
  3. Instituto de Biología Molecular de Barcelona, Spain
  4. Charles University, Czech Republic
  5. National Cancer Institute, United States
  6. Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Spain
  7. University of Barcelona, Spain
  8. 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

The following data sets were generated

Article and author information

Author details

  1. Ilaria Dutto

    Institute for Research in Biomedicine, Barcelona, Spain
    Competing interests
    No competing interests declared.
  2. Julian Gerhards

    Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University of Tubingen, Tubingen, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7005-1618
  3. Antonio Herrera

    Department of Cell Biology, Instituto de Biología Molecular de Barcelona, Barcelona, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6248-1001
  4. Olga Souckova

    Department of Paediatrics and Inherited Metabolic Disorders, Charles University, Prague, Czech Republic
    Competing interests
    No competing interests declared.
  5. Václava Škopová

    Department of Paediatrics and Inherited Metabolic Disorders, Charles University, Prague, Czech Republic
    Competing interests
    No competing interests declared.
  6. Jordann Smak

    Center for Cancer Research, Radiation Oncology Branch, National Cancer Institute, Bethesda, United States
    Competing interests
    No competing interests declared.
  7. Alexandra Junza

    Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Madrid, Spain
    Competing interests
    No competing interests declared.
  8. Oscar Yanes

    Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Madrid, Spain
    Competing interests
    No competing interests declared.
  9. Cedric Boeckx Prof

    Institute of Complex Systems, University of Barcelona, Barcelona, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8882-9718
  10. Martin D Burkhalter

    Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University of Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8646-3131
  11. Marie Zikánová

    Department of Paediatrics and Inherited Metabolic Disorders, Charles University, Prague, Czech Republic
    Competing interests
    No competing interests declared.
  12. Sebastian Pons

    Department of Cell Biology, Instituto de Biología Molecular de Barcelona, Barcelona, Spain
    Competing interests
    No competing interests declared.
  13. Melanie Philipp

    Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University of Tubingen, Tubingen, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2714-965X
  14. Jens Lüders

    Institute for Research in Biomedicine, Barcelona, Spain
    Competing interests
    Jens Lüders, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9018-7977
  15. Travis H Stracker

    Center for Cancer Research, Radiation Oncology Branch, National Cancer Institute, Bethesda, United States
    For correspondence
    travis.stracker@nih.gov
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8650-2081

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.

Reviewing Editor

  1. Fadel Tissir, Université Catholique de Louvain, Belgium

Publication history

  1. Preprint posted: November 23, 2020 (view preprint)
  2. Received: May 26, 2021
  3. Accepted: December 22, 2021
  4. Accepted Manuscript published: February 8, 2022 (version 1)
  5. Accepted Manuscript updated: February 9, 2022 (version 2)
  6. Version of Record published: February 24, 2022 (version 3)
  7. Version of Record updated: March 18, 2022 (version 4)
  8. Version of Record updated: September 16, 2022 (version 5)

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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  1. Ilaria Dutto
  2. Julian Gerhards
  3. Antonio Herrera
  4. Olga Souckova
  5. Václava Škopová
  6. Jordann Smak
  7. Alexandra Junza
  8. Oscar Yanes
  9. Cedric Boeckx Prof
  10. Martin D Burkhalter
  11. Marie Zikánová
  12. Sebastian Pons
  13. Melanie Philipp
  14. Jens Lüders
  15. Travis H Stracker
(2022)
Pathway specific effects of ADSL deficiency on neurodevelopment
eLife 11:e70518.
https://doi.org/10.7554/eLife.70518
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