Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction.

Maia Lanfranco,Neville Vassallo,Ruben J Cauchi

doi:10.3389/fmolb.2017.00041

Abstract

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN) protein. SMN is part of a multiprotein complex that also includes Gemins 2–8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5) complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs) to generate small nuclear ribonucleoproteins (snRNPs), which are the operating components of the spliceosome. Molecular and structural studies have refined our knowledge of the key events taking place within the crowded environment of cells and the numerous precautions undertaken to ensure the faithful assembly of snRNPs. Nonetheless, it remains unclear whether a loss of chaperoning in snRNP assembly, considered as a “housekeeping” activity, is responsible for the selective neuromuscular phenotype in SMA. This review thus shines light on in vivo studies that point toward disturbances in snRNP assembly and the consequential transcriptome abnormalities as the primary drivers of the progressive neuromuscular degeneration underpinning the disease. Disruption of U1 snRNP or snRNP assembly factors other than SMN induces phenotypes that mirror aspects of SMN deficiency, and splicing defects, described in numerous SMA models, can lead to a DNA damage and stress response that compromises the survival of the motor system. Restoring the correct chaperoning of snRNP assembly is therefore predicted to enhance the benefit of SMA therapeutic modalities based on augmenting SMN expression.

Highlights

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that can afflict both infants and adults
A single nucleotide substitution (C/T) in exon 7, converts an exon splicing enhancer to a silencer, inducing the omission of exon 7 from most of the SMN2-derived mRNA transcripts. This alteration leads to the production of an unstable truncated protein isoform (SMN 7) that is rapidly degraded, in the absence of complete penetrance, fulllength, functional survival motor neuron (SMN) is still encoded by a small portion of SMN2 transcripts that evade exon 7 skipping
The antisense oligonucleotide (ASO) nusinersen, recently approved for a broad patient population, is the first successful output of a campaign aimed at identifying therapeutics that promote exon 7 inclusion in SMN2 transcripts

Summary

INTRODUCTION

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that can afflict both infants and adults. The same outcome applies to additional SMN-Gemins complex members investigated far To this end, knockout or RNAi-mediated knockdown of Gemin, Gemin or Gemin leads to lethality in various organisms (reviewed in Borg and Cauchi, 2014). Knockout or RNAi-mediated knockdown of Gemin, Gemin or Gemin leads to lethality in various organisms (reviewed in Borg and Cauchi, 2014) This might indicate that the constituents of the SMN-Gemins complex are not redundant, the function of one component cannot be covered by another. The upregulation of SMN or Gemin can have a negative impact on fly viability only when either perturbation is combined with a Gemin hypomorphic mutant (Borg et al, 2015) These findings are in line with studies that underscore the interdependence of constituent levels within the SMN-Gemins complex. The half-life of SMN was decreased by mutations interfering with its incorporation within the SMN-Gemins complex (Burnett et al, 2009)

A REFINED VIEW OF CHAPERONING ACTIVITIES DURING snRNP BIOGENESIS

CONCLUSION