Identification and correction of the molecular and cellular defects in neurons caused by deregulation of the novel autism susceptibility gene EIF4E – an opportunity to develop treatments for autism

Autism is an as yet untreatable common lifelong childhood onset neurodevelopmental disorder affecting 1 out of every 200 individuals. The underlying genetics is complex and poorly understood. We have identified EIF4E as an autism susceptibility gene. In addition, mutations in several genes known to control the activity of eIF4E protein cause autism or syndromes with autistic features (see attached Figure 1). Together this strongly supports our hypothesis that over-expression of eIF4E protein predisposes to autism, and we propose that correction of eIF4E over-expression could form the basis of effective treatment of autism. To test this we will identify the abnormalities caused by eIF4E over-expression in neurons using two complementary approaches: we will determine the effect of eIF4E over-expression on the differentiation and behaviour of neurons using live cell microscopy and immunocytochemistry, and we will identify changes in protein components caused by eIF4E over-expression using state of the art protein profiling methods. Together, this will increase our understanding of the underlying molecular events leading to the development of autism. We will produce reagents for the detection of proteins whose levels are changed, as they may serve as marker proteins for autism. Finally, we will test whether any changes occurring in neurons when eIF4E is over-expressed can be reversed by compounds known to control eIF4E activity. This work will produce reagents to identify subjects with autism caused by dysregulation of eIF4E and will lead to screens that are expected to identify novel compounds to treat this condition.