PUBLICATION
Pathway specific effects of ADSL deficiency on neurodevelopment
- Authors
- Dutto, I., Gerhards, J., Herrera, A., Souckova, O., Škopová, V., Smak, J., Junza, A., Yanes, O., Boeckx, C., Burkhalter, M.D., Zikánová, M., Pons, S., Philipp, M., Lüders, J., Stracker, T.H.
- ID
- ZDB-PUB-220209-9
- Date
- 2022
- Source
- eLIFE 11: (Journal)
- Registered Authors
- Philipp, Melanie
- Keywords
- cell biology, chicken, developmental biology, human, zebrafish
- MeSH Terms
-
- Adenylosuccinate Lyase/deficiency*
- Adenylosuccinate Lyase/metabolism*
- Aminoimidazole Carboxamide/analogs & derivatives
- Aminoimidazole Carboxamide/metabolism
- Animals
- Autism Spectrum Disorder/metabolism
- Autistic Disorder/metabolism*
- Cell Cycle
- Cell Cycle Proteins/metabolism
- Cell Line
- Chickens/metabolism
- Ciliopathies/metabolism
- DNA Damage
- Humans
- Microcephaly/metabolism
- Microtubule-Associated Proteins/metabolism
- Neurogenesis*
- Phenotype
- Phosphoproteins/metabolism
- Purine-Pyrimidine Metabolism, Inborn Errors/metabolism*
- Purines/metabolism
- Ribonucleotides/metabolism
- Zebrafish/metabolism
- PubMed
- 35133277 Full text @ Elife
Citation
Dutto, I., Gerhards, J., Herrera, A., Souckova, O., Škopová, V., Smak, J., Junza, A., Yanes, O., Boeckx, C., Burkhalter, M.D., Zikánová, M., Pons, S., Philipp, M., Lüders, J., Stracker, T.H. (2022) Pathway specific effects of ADSL deficiency on neurodevelopment. eLIFE. 11:.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping