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

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• The AGAP1 gene encodes an Arf1 GTPase-activating protein crucial for endolysosomal trafficking.
• Pathogenic variants in AGAP1 have been associated with neurodevelopmental conditions such as autism and cerebral palsy.
• Three new individuals with microdeletion variants in AGAP1 present with intellectual disability, autism, and other developmental abnormalities.

Approach:

• Investigated the functional consequences of AGAP1 variants using a Drosophila melanogaster model, focusing on the orthologous gene CenG1a.
• Examined synaptic morphology, endosomal trafficking, autophagy, and the integrated stress response in mutant flies.
• Assessed gene-environment interactions by exposing mutant flies to cytotoxic stressors.

Key Points:

• AGAP1 deficiency leads to impaired endolysosomal trafficking, characterized by reduced axon terminal size and increased neuronal endosome abundance.
• Mutant flies exhibit chronic autophagy induction and basal activation of the integrated stress response protein eIF2α-P.
• AGAP1-deficient cells show heightened susceptibility to environmental insults, indicating a role for gene-environment interactions in neurodevelopmental outcomes.

Conclusions:

• Disruption of AGAP1 impairs endolysosomal trafficking, chronically activates the integrated stress response, and sensitizes cells to secondary environmental stressors.
• This mechanism provides a potential model for neurodevelopmental disorders arising from combined genetic and environmental factors.
• The findings highlight the importance of AGAP1 in neuronal development and suggest broader implications for understanding complex neurodevelopmental disorders.