The SMN Complex at the Crossroad between RNA Metabolism and Neurodegeneration

In the cell, RNA exists and functions in a complex with RNA binding proteins (RBPs) that regulate each step of the RNA life cycle from transcription to degradation. Central to this regulation is the role of several molecular chaperones that ensure the correct interactions between RNA and proteins, while aiding the biogenesis of large RNA-protein complexes (ribonucleoproteins or RNPs). Accurate formation of RNPs is fundamentally important to cellular development and function, and its impairment often leads to disease. The survival motor neuron (SMN) protein exemplifies this biological paradigm. SMN is part of a multi-protein complex essential for the biogenesis of various RNPs that function in RNA metabolism. Mutations leading to SMN deficiency cause the neurodegenerative disease spinal muscular atrophy (SMA). A fundamental question in SMA biology is how selective motor system dysfunction results from reduced levels of the ubiquitously expressed SMN protein. Recent clarification of the central role of the SMN complex in RNA metabolism and a thorough characterization of animal models of SMA have significantly advanced our knowledge of the molecular basis of the disease. Here we review the expanding role of SMN in the regulation of gene expression through its multiple functions in RNP biogenesis. We discuss developments in our understanding of SMN activity as a molecular chaperone of RNPs and how disruption of SMN-dependent RNA pathways can contribute to the SMA phenotype.

Automated summary

RNA exists and functions with RNA binding proteins (RBPs) in a cell to regulate the RNA life cycle. Molecular chaperones play a central role in this regulation by ensuring correct interactions and aiding the biogenesis of large RNA-protein complexes. Impairment of accurate formation of these complexes can lead to disease. The survival motor neuron (SMN) protein is an example of this, with deficiency causing spinal muscular atrophy (SMA). Understanding the role of SMN in gene expression and disruption of SMN-dependent RNA pathways is important for understanding SMA.