SMN in spinal muscular atrophy and snRNP biogenesis

Abstract

Ribonucleoprotein (RNP) complexes function in nearly every facet of cellular activity. The spliceosome is an essential RNP that accurately identifies introns and catalytically removes the intervening sequences, providing exquisite control of spatial, temporal, and developmental gene expressions. U-snRNPs are the building blocks for the spliceosome. A significant amount of insight into the molecular assembly of these essential particles has recently come from a seemingly unexpected area of research: neurodegeneration. Survival motor neuron (SMN) performs an essential role in the maturation of snRNPs, while the homozygous loss of SMN1 results in the development of spinal muscular atrophy (SMA), a devastating neurodegenerative disease. In this review, the function of SMN is examined within the context of snRNP biogenesis and evidence is examined which suggests that the SMN functional defects in snRNP biogenesis may account for the motor neuron pathology observed in SMA.

A new cis-acting motif is required for the axonal SMN-dependent Anxa2 mRNA localization

“…Several studies have reported that SMN deficiency alters the stoichiometry of snRNAs and causes widespread and differential pre-mRNA splicing defects (Gabanella et al 2007;Zhang et al 2008;Boulisfane et al 2011;Lotti et al 2012). These results support the view that SMA might arise from the inefficient splicing of pre-mRNAs coding for proteins required for motor neuron's function and/or organization (Burghes and Beattie 2009;Coady and Lorson 2011;Li et al 2014). However, whether such splicing defects are directly caused by SMN loss or are secondary effects of cellular dysfunction is still unknown (Bäumer et al 2009;Garcia et al 2013).…”

Genome-wide identification of mRNAs associated with the protein SMN whose depletion decreases their axonal localization

“…2A). The presence of noncoding RNAs, e.g., snRNAs, snoRNAs, scaRNAs, and rRNAs, was anticipated, given the well-established role of SMN in snRNP biogenesis and in the formation of Cajal bodies, along with numerous studies reporting interactions of the SMN protein with proteins of snoRNPs or its localization in specific subnucleolar structures (Terns and Terns 2001;Cioce and Lamond 2005;Chari et al 2009;Coady and Lorson 2011). The association of tRNAs and miRNAs with SMN is likely explained by the observations that components of the SMN complex, such as Gemin4 and Gemin5, are present in different complexes containing numerous miRNAs (Mourelatos et al 2002) and involved in the modulation of translation activity (Pacheco et al 2009), respectively.…”

“…The SMN protein is part of a large complex comprising Unrip and seven Gemin proteins (Gemins 2-8) that is essential for the biogenesis of small nuclear ribonucleoprotein particles (snRNPs) (Fischer et al 1997;Pellizzoni et al 1998;Meister et al 2000; for review, see Coady and Lorson 2011;Workman et al 2012). These particles are major components of the spliceosome, the machinery that carries out pre-mRNA splicing (Wahl et al 2009).…”

Recent Advances in Understanding of Alternative Splicing in Neuronal Pathogenesis

“…Indeed, SMN participates in snRNP biogenesis, which is an important housekeeping function, and also in splicing, transcription, and neuronal mRNA trafficking Coady & Lorson, 2011) (Figure 3). In the nucleus, SMN is particularly concentrated in discrete nuclear bodies that are very close to Cajal bodies (Carvalho, et al, 1999;Young, et al, 2000).…”

“…Assembly of the heptameric Sm cores with each spliceosomal snRNA occurs in a highly ordered manner Cauchi, 2010;Coady & Lorson, 2011). Initially, the chaperon factor pICln brings methylated Sm protein subcomplexes to the SMN complex, which is composed of SMN, Gemin2-8, and unr-interacting proteins.…”