GEMINs: potential therapeutic targets for spinal muscular atrophy?

Abstract

The motor neuron degenerative disease spinal muscular atrophy (SMA) remains one of the most frequently inherited causes of infant mortality. Afflicted patients loose the survival motor neuron 1 (SMN1) gene but retain one or more copies of SMN2, a homolog that is incorrectly spliced. Primary treatment strategies for SMA aim at boosting SMN protein levels, which are insufficient in patients. SMN is known to partner with a set of diverse proteins collectively known as GEMINs to form a macromolecular complex. The SMN-GEMINs complex is indispensible for chaperoning the assembly of small nuclear ribonucleoproteins (snRNPs), which are key for pre-mRNA splicing. Pharmaceutics that alleviate the neuromuscular phenotype by restoring the fundamental function of SMN without augmenting its levels are also crucial in the development of an effective treatment. Their use as an adjunct therapy is predicted to enhance benefit to patients. Inspired by the surprising discovery revealing a premier role for GEMINs in snRNP biogenesis together with in vivo studies documenting their requirement for the correct function of the motor system, this review speculates on whether GEMINs constitute valid targets for SMA therapeutic development.

Keywords: GEMINs; SMN-GEMINs complex; motor neuron degeneration; motor neuron disease; small nuclear ribonucleoprotein assembly; spinal muscular atrophy; survival motor neuron; treatment strategies.

Figure 1

SMN and GEMINs: protein interactions and motor system requirements. (A) Circular representation of the intricate web of interactions between members of the SMN-GEMINs complex in vertebrates. Ribbons shown in colors specific to each complex member indicate interactions verified in more than one experimental system. Black ribbons specify interactions in only one experimental system (based on data reviewed in Cauchi, 2010). (B) Degree of overlap between specific Gemins and SMN with respect to organismal viability on enhanced RNAi-mediated knockdown starting early during development in Drosophila (based on data featured in Borg and Cauchi, 2013). With regards to SMN, the N4 RNAi strain developed by Chang et al. (2008) was utilized for comparison. With the exception of Gemin2 within the CNS, there is a similar requirement for both Gemins and SMN in the motor system. Width of the ribbons is inversely proportional to viability (the wider the ribbon, the lower the viability). Ribbon color corresponds to the tissue in which knockdown is restricted. Graphics in (A,B) were built using Circos (Krzywinski et al., 2009).