Spinal muscular atrophy: the role of SMN in axonal mRNA regulation

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by homozygous mutations or deletions in the survival of motor neuron (SMN1) gene, encoding the ubiquitously expressed SMN protein. SMN associates with different proteins (Gemins 2-8, Unrip) to form a multimeric complex involved in the assembly of small nuclear ribonucleoprotein complexes (snRNPs). Since this activity is essential for the survival of all cell types, it still remains unclear why motor neurons are selectively vulnerable to low levels of SMN protein. Aside from its housekeeping role in the assembly of snRNPs, additional functions of SMN have been proposed. The well-documented localization of SMN in axonal transport granules and its interaction with numerous mRNA-binding proteins not involved in splicing regulation suggest a role in axonal RNA metabolism. This review will focus on the neuropathological and experimental evidence supporting a role for SMN in regulating the assembly, localization, or stability of axonal messenger ribonucleoprotein complexes (mRNPs). Furthermore, how defects in this non-canonical SMN function may contribute to the motor neuron pathology observed in SMA will be discussed. This article is part of a Special Issue entitled RNA-Binding Proteins.

Figure 1. Neuropathological hallmarks of SMA

Schematic representation of anatomical findings linked to reduced SMN levels in human SMA patients and in SMA animals. Spinal motor neurons located in the anterior horn of the spinal cord show increased cell death, defective innervation of the target skeletal muscle, and reduction in the number of afferent synapses with proprioceptive neurons. Also, heterotopic motor neurons located around the gray matter of the anterior horn have been reported in humans (Simic et al., 2008). Neuromuscular junctions (NMJs) in SMA are characterized by neurofilament (NF) aggregates, reduced neurotransmitter (NT) release, a delayed switch to adult acetylcholine receptor (AChR) subunits, and signs of denervation.

Figure 2. Molecular functions of SMN

Schematic representation of the proposed functions for SMN in neurons. SMN, present as part of the classical SMN complex, plays an essential role in small nuclear ribonucleoprotein (snRNP) biogenesis. An additional function in the assembly of mRNA-containing RNPs has been proposed, whereby SMN facilitates the recognition of RNA-binding proteins with their targets, and their transport along motor neuron axons.