Pathway-specific effects of ADSL deficiency on neurodevelopment

Area of Science:

• Biochemistry
• Neuroscience
• Genetics

Background:

• Adenylosuccinate lyase (ADSL) is crucial for de novo purine synthesis (DNPS) and the purine nucleotide cycle.
• ADSL deficiency (ADSLD) leads to neurodevelopmental disorders, including microcephaly and autism spectrum disorder.
• Patients with ADSLD show normal serum purine nucleotides but accumulate dephosphorylated substrates like SAICAr, linked to neurotoxicity.

Purpose of the Study:

• To investigate the phenotypic effects of ADSL depletion in human cells.
• To explore the relationship between ADSL depletion, purine levels, SAICAr accumulation, and neurodevelopmental outcomes.
• To elucidate the mechanisms underlying ADSLD-related pathologies.

Main Methods:

• Utilized human cell models to study ADSL depletion.
• Employed interventions to modulate purine levels and SAICAr accumulation.
• Examined ADSL-deficient chicken and zebrafish embryos.
• Used pharmacological inhibition of DNPS in zebrafish models.

Main Results:

• Diminished AMP levels caused DNA damage signaling and cell cycle delays.
• Primary ciliogenesis was impaired by ADSL loss or SAICAr administration.
• ADSL-deficient embryos showed impaired neurogenesis and microcephaly.
• DNPS inhibition rescued neuroprogenitor attrition in zebrafish, unlike nucleotide concentration increase.
• Zebrafish exhibited phenotypes associated with ciliopathies.

Conclusions:

• Both reduced purine levels and impaired DNPS contribute to neurodevelopmental pathology in ADSLD.
• Defective ciliogenesis is implicated in the spectrum of ADSLD phenotypes.
• SAICAr accumulation and impaired purine synthesis pathways are key drivers of ADSLD neurotoxicity.