RNA-binding proteins balance brain function in health and disease

Abstract

Posttranscriptional gene expression including splicing, RNA transport, translation, and RNA decay provides an important regulatory layer in many if not all molecular pathways. Research in the last decades has positioned RNA-binding proteins (RBPs) right in the center of posttranscriptional gene regulation. Here, we propose interdependent networks of RBPs to regulate complex pathways within the central nervous system (CNS). These are involved in multiple aspects of neuronal development and functioning, including higher cognition. Therefore, it is not sufficient to unravel the individual contribution of a single RBP and its consequences but rather to study and understand the tight interplay between different RBPs. In this review, we summarize recent findings in the field of RBP biology and discuss the complex interplay between different RBPs. Second, we emphasize the underlying dynamics within an RBP network and how this might regulate key processes such as neurogenesis, synaptic transmission, and synaptic plasticity. Importantly, we envision that dysfunction of specific RBPs could lead to perturbation within the RBP network. This would have direct and indirect (compensatory) effects in mRNA binding and translational control leading to global changes in cellular expression programs in general and in synaptic plasticity in particular. Therefore, we focus on RBP dysfunction and how this might cause neuropsychiatric and neurodegenerative disorders. Based on recent findings, we propose that alterations in the entire regulatory RBP network might account for phenotypic dysfunctions observed in complex diseases including neurodegeneration, epilepsy, and autism spectrum disorders.

Keywords: autism; epilepsy; intellectual disabilities; local protein synthesis; synaptic dysfunction; synaptic plasticity.