The Survival of Motor Neuron Protein Acts as a Molecular Chaperone for mRNP Assembly

Abstract

Summary Spinal muscular atrophy (SMA) is a motor neuron disease caused by reduced levels of the survival of motor neuron (SMN) protein. SMN is part of a multiprotein complex that facilitates the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). SMN has also been found to associate with mRNA binding proteins but the nature of this association was unknown. Here we have employed a combination of biochemical and advanced imaging methods to demonstrate that SMN promotes the molecular interaction between IMP1 protein and the 3′ UTR zipcode region of β-actin mRNA, leading to assembly of messenger ribonucleoprotein complexes (mRNPs) that associate with the cytoskeleton to facilitate trafficking. We have identified defects in mRNP assembly in cells and tissues from SMA disease models and patients that depend on the SMN Tudor domain and explain the observed deficiency in mRNA localization and local translation, providing insight into SMA pathogenesis as an RNP-assembly disorder.

Neuronal ribonucleoprotein granules: Dynamic sensors of localized signals

“…Hypo‐assembly diseases are part of a diffuse spectrum of disorders associated either with RNA degradation or loss of molecular chaperones . To date, the best described example is spinal muscular atrophy (SMA), a motor neuron degenerative disease caused by the inactivation of the SMN1 gene, which encodes an RNA‐associated protein involved in the assembly of spliceosomal small ribonucleoprotein complexes (snRNPs), and in the efficient recruitment of RBPs into axonally transported neuronal RNP granules . Although the pathological mechanisms underlying specific motor neuron degeneration are still under debate, they may include defective splicing of critical neuronal genes and defective axonal transport of neuronal RNP granules …”

Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

“…SMN has a well-characterized role in the assembly of small nuclear ribonucleoproteins (snRNPs) of the splicing machinery (Meister et al, 2001;Pellizzoni et al, 2002) as well as the U7 snRNP, which functions in 3 0 end processing of histone mRNAs (Pillai et al, 2003;Tisdale et al, 2013). SMN has also been implicated in other aspects of RNA regulation including mRNA transport (Donlin-Asp et al, 2017). Consistent with its central role in RNA processing (Donlin-Asp et al, 2016;Li et al, 2014), SMN deficiency has been shown to induce widespread splicing dysregulation and transcriptome alterations in a variety of in vivo models (Bä umer et al, 2009;Doktor et al, 2017;Jangi et al, 2017;Zhang et al, 2008Zhang et al, , 2013.…”

Impact of RNA–Protein Interaction Modes on Translation Control: The Versatile Multidomain Protein Gemin5

“…However, splicing defects in SMA models are found throughout different tissues, suggesting that SMA pathogenesis relies on additional RNA‐related pathways occurring in neurons. In fact, SMN is a multifunctional protein involved in ribosomal RNA biogenesis, processing of mRNAs, mRNA transport, and translation control …”