AGAP1-associated endolysosomal trafficking abnormalities link gene-environment interactions in neurodevelopmental...

Area of Science:

• Genetics
• Neuroscience
• Cell Biology

Background:

• The AGAP1 gene encodes an Arf1 GTPase-activating protein crucial for endolysosomal trafficking.
• Damaging variants in AGAP1 are associated with neurodevelopmental conditions, including cerebral palsy and autism spectrum disorder.
• Three new cases of microdeletion variants in AGAP1 are presented, highlighting associated neurodevelopmental phenotypes.

Purpose of the Study:

• To investigate the mechanisms underlying AGAP1 variant-mediated neurodevelopmental impairments.
• To explore the role of gene-environment interactions in AGAP1-related disorders.
• To establish a model for AGAP1-deficiency-related cellular dysfunction.

Main Methods:

• Clinical case reporting of individuals with AGAP1 microdeletions.
• Utilizing the Drosophila ortholog CenG1a to model AGAP1 function and dysfunction.
• Assessing neuronal morphology, endolysosomal trafficking, autophagy, and integrated stress response pathways in mutant flies.
• Evaluating gene-environment interactions through exposure to cytotoxic stressors.

Main Results:

• Affected individuals presented with intellectual disability, autism, dystonia, brain maturation abnormalities, growth impairment, and facial dysmorphism.
• Drosophila models showed reduced axon terminal size, increased neuronal endosome abundance, and elevated autophagy.
• AGAP1 deficiency led to chronic activation of the integrated stress response (eIF2α phosphorylation) and impaired stress response to further insults.
• Mutant flies exhibited increased lethality upon exposure to environmental stressors, indicating compromised resilience.

Conclusions:

• Disruption of AGAP1 impairs endolysosomal trafficking, leading to chronic integrated stress response activation.
• AGAP1 deficiency renders cells vulnerable to secondary environmental insults, contributing to neurodevelopmental disorders.
• The proposed model of gene-environment interaction may be relevant for other neurodevelopmental disorders involving combined genetic and environmental factors.