RNA-binding proteins, neural development and the addictions

Transcriptional and post-transcriptional regulation of gene expression defines the neurobiological mechanisms that bridge genetic and environmental risk factors with neurobehavioral dysfunction underlying the addictions. More than 1000 genes in the eukaryotic genome code for multifunctional RNA-binding proteins (RBPs) that can regulate all levels of RNA biogenesis. More than 50% of these RBPs are expressed in the brain where they regulate alternative splicing, transport, localization, stability and translation of RNAs during development and adulthood. Dysfunction of RBPs can exert global effects on their targetomes that underlie neurodegenerative disorders such as Alzheimer's and Parkinson's diseases as well as neurodevelopmental disorders, including autism and schizophrenia. Here, we consider the evidence that RBPs influence key molecular targets, neurodevelopment, synaptic plasticity and neurobehavioral dysfunction underlying the addictions. Increasingly well-powered genome-wide association studies in humans and mammalian model organisms combined with ever more precise transcriptomic and proteomic approaches will continue to uncover novel and possibly selective roles for RBPs in the addictions. Key challenges include identifying the biological functions of the dynamic RBP targetomes from specific cell types throughout subcellular space (e.g. the nuclear spliceome vs. the synaptic translatome) and time and manipulating RBP programs through post-transcriptional modifications to prevent or reverse aberrant neurodevelopment and plasticity underlying the addictions.