Regulation of neuronal translation in Autism Spectrum Disorders
Proteins catalyze most of the reactions in the cell on which life depends as they serve numerous functions, including enzymes, structure, energy production and many others. Thus, a large proportion of the cell's resources is devoted to the process of synthesis of proteins, called translation. Translation is a multistep process that is mainly regulated at the first step called initiation. The investigator's laboratory has, for more than 30 years, focused on how this process is controlled and how misregulation leads to pathological conditions like cancer, obesity and memory impairment. The research team has acquired evidence that a key molecule in the regulation of translation initiation (called 4E-BP2) is implicated in the development of autistic behaviors in a genetic knockout mouse model, including impaired social interaction, reduced preference for social novelty and compulsive behaviour, along with alterations in the anatomical characteristics, as demonstrated by increased complexity of neuronal processes. These changes have been extensively observed in other mouse models of autism and are reminiscent of pathological findings in Autism Spectrum Disorders (ASD) patients. In addition, 4E-BP2 integrates inputs from many molecular pathways of neurons and is implicated in learning and memory and neurodegenerative disease. They have also recently showed that 4E-BP2 function can be modulated by a brain-specific chemical modification, which is developmentally regulated in the mammalian brain. This study aims to examine the involvement of 4E-BP2 in autism using a combination of genetic and molecular approaches. Using FDA approved drugs (rapamycin, an anticancer drug that targets 4E-BP2 with high specificity and metformin an antidiabetic drug that targets the same pathway) along with new generation inhibitors, the investigators will examine whether the autistic behaviors and cellular alterations they observe in the 4E-BP2 knockout mouse model can be reversed. Furthermore, they will identify new biomarkers/risk genes by gene expression analysis of brain tissue from the 4E-BP2 knockout mice. Finally, the investigators will investigate the molecular mechanism of 4E-BP2 brain specific regulation by characterizing the novel chemical modification of 4E-BP2 in regards to autism. In summary, this Pilot study will investigate how translational control in neurons can lead to ASD, which will increase our understanding of the molecular underpinnings of autism.