Brain development and function require adaptive control of protein synthesis (mRNA translation), which is often disrupted in autism spectrum disorder (ASD). Genetic and environmental factors are implicated in ASD etiology. Two genes which are considered high-confidence risk factors for ASD (category 1 in the SFARI Gene database and a probability of loss-of-function intolerance score of 1) are GIGYF1 and GIGYF2. GIGYF1/2 proteins directly interact with the Eukaryotic Translation Initiation Factor 4E Family Member 2 homologous protein (4EHP, encoded by the gene EIF4E2). 4EHP binds to the 5’ cap structure (m7GpppN, where N is any nucleotide, and m is a methyl group) and acts to repress mRNA translation or decrease mRNA stability.
There is evidence that the GIGYF1/2-4EHP complex is involved in translation regulation pathways, which are critical for ribosome-associated quality control (RQC), microRNA-mediated mRNA translational repression and nonsense-mediated mRNA decay (NMD). Recent pilot studies conducted in Sonenberg’s laboratory have provided preliminary evidence that the GIGYF1/2-4EHP complex regulates these pathways via microRNA silencing or local translational regulation in specific neuronal types. Sonenberg hypothesizes that mutations in GIGYF1/2 disrupt the function of the GIGYF1/2-4EHP translation repression, thus resulting in dysregulation of protein synthesis leading to aberrant synaptic function and susceptibility to behavioral impairments.
Sonenberg and colleagues will use excitatory and inhibitory pathway specific Gigyf1/2 conditional knockout mice to address the urgent need to unravel their specific roles. The project will leverage the extensive resources and experienced personnel of the Sonenberg lab to investigate the cellular and behavioral impact of Gigyf1/2 from two directions simultaneously. Aim 1 will explore the outcomes on behaviors relevant to ASD (e.g., social and repetitive behaviors) and synaptic plasticity of the conditional knockout Gigyf1/2 mice in the brain. Aim 2 will investigate the effect of ASD-linked GIGYF1/2 mutations on the translational efficiency and expression levels of key components of the microRNA, RQC and NMD pathways via ribosome profiling and proteomics.
The research will provide novel insight into the molecular mechanisms of GIGYF1/2 and downstream consequences when these proteins are mutated. The results will form a basis for better genetic screening and future development of treatments for ASD.
