RNA-binding proteins in neurological diseases

Abstract

Emerging studies support that RNA-binding proteins (RBPs) play critical roles in human biology and pathogenesis. RBPs are essential players in RNA processing and metabolism, including pre-mRNA splicing, polyadenylation, transport, surveillance, mRNA localization, mRNA stability control, translational control and editing of various types of RNAs. Aberrant expression of and mutations in RBP genes affect various steps of RNA processing, altering target gene function. RBPs have been associated with various diseases, including neurological diseases. Here, we mainly focus on selected RNA-binding proteins including Nova-1/Nova-2, HuR/HuB/HuC/HuD, TDP-43, Fus, Rbfox1/Rbfox2, QKI and FMRP, discussing their function and roles in human diseases.

Dysregulation of mRNA Localization and Translation in Genetic Disease

“…Jung et al, 2014). RBPs play critical roles during these processes by regulating RNA metabolism to modify gene expression in neurons (Zhou et al, 2014). This idea gains further support from human genetic studies that show that mutations in the genes of several RBPs are associated with neurological diseases (Liu-Yesucevitz et al, 2011;Gao and Taylor, 2014).…”

“…Drosophila cytoplasmic RBFOX1 represses translation of one of its target mRNAs, the translational regulator pumilio, to regulate germ cell differentiation (Carreira-Rosario et al, 2016), indicating that RBFOX1 may either enhance or repress gene expression in the cytoplasm of cells. Recent studies showed that RBFOX2 and RBFOX3 can regulate the biogenesis of microRNAs, and RBFOX2 can bind nascent RNAs to regulate polycomb complex 2 targeting Wei et al, 2016). These data suggest that RBPs might have diverse functions in neurons and an increased understanding of RNA regulation will lead to novel therapies for a range of brain disorders.…”

“…Reduced SMN protein levels cause SMA, which is characterized by axonal dying back of spinal motor neurons leading to muscular atrophy and typically death in early childhood. While widespread splicing defects occur in all SMA models characterized thus far (Gabanella et al, 2007;Zhang et al, 2008Lotti et al, 2012), the role of these defects in the disease process may very well represent a secondary nonspecific effect of neurodegeneration, and their significance for SMA pathogenesis remains to be fully elucidated (Bäumer et al, 2009).…”

“…In such RNA granule assemblies, sequestered and translationally repressed mRNAs are transported on cytoskeletal filaments to specific intracellular locations (Kiebler and Bassell, 2006;Zeitelhofer et al, 2008). In neurons, activity-induced disassembly of RNP granules plays an important physiological role to enable local translation of dendritically localized mRNAs (Krichevsky and Kosik, 2001; H. Wang and Tiedge, 2004;Zeitelhofer et al, 2008).…”

Introduction to the thematic issue “From brain function to therapy”

“…Also focussed on neurodegenerative diseases such as motor neuron disease, Professor Wu Jane (IBP) and Dr Marie Mangelsdorf (QBI) provide insights into the role played by aberrant expression and mutation of genes coding for RNA-binding proteins in initiating human brain disease [9].…”