Translatome analysis in postmortem brain-derived samples from Autism Spectrum Disorder affected individuals
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic link, but no single well-established cause. This suggests that perturbed regulatory network may better explain its heterogeneity of phenotypes and multiple gene associations. Consistently, our previous study provided evidence of abnormal alternative polyadenylation in transcripts from distinct brain regions suggesting a potential imbalance in the protein synthesis in the postsynaptic density. To test this hypothesis, we studied transcriptome-wide alterations of mRNA translation in post-mortem brain samples from neurotypical and ASD-affected young males subjects. To this end, we employed an optimised polysome profiling technique amendable for small tissue samples and analyzed changes in the translatome using the anota2seq algorithm. The analysis revealed bolstered translation of mRNAs whose translational efficiency was previously reported to be sensitive to eIF4E, a key factor for synaptic protein synthesis modulated by Ras/ERK and PI3K/mTOR signaling pathways. This observation is consistent with previous findings linking hyperactive eIF4E to increased translation of neuroligins, a disturbed excitation/inhibition ratio in synapses and autistic-like phenotypes in mice. In summary, we reveal a link between eIF4E-dependent translation and human autism, indicating a potential pharmacy-therapeutical target for the prevention of behavioral impairments in ASD. Overall design: 10 brain samples were collected post-mortem from neurotypical and ASD-affected donors (NIH NeuroBioBank). To minimize study bias, the donors were matched for age (4-9 years old) and sex (male); and samples only originated from Brodmann Area 19.