Spinal muscular atrophy and a model for survival of motor neuron protein function in axonal ribonucleoprotein complexes

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease that results from loss of function of the SMN1 gene, encoding the ubiquitously expressed survival of motor neuron (SMN) protein, a protein best known for its housekeeping role in the SMN-Gemin multiprotein complex involved in spliceosomal small nuclear ribonucleoprotein (snRNP) assembly. However, numerous studies reveal that SMN has many interaction partners, including mRNA binding proteins and actin regulators, suggesting its diverse role as a molecular chaperone involved in mRNA metabolism. This review focuses on studies suggesting an important role of SMN in regulating the assembly, localization, or stability of axonal messenger ribonucleoprotein (mRNP) complexes. Various animal models for SMA are discussed, and phenotypes described that indicate a predominant function for SMN in neuronal development and synapse formation. These models have begun to be used to test different therapeutic strategies that have the potential to restore SMN function. Further work to elucidate SMN mechanisms within motor neurons and other cell types involved in neuromuscular circuitry hold promise for the potential treatment of SMA.

Fig. 1

SMN1 exon boundaries and protein domain structure. Top: SMN1 is encoded by 9 exons. Coding regions are indicated in cyan and untranslated regions in purple. Bottom: Domains required for oligomerization of SMN are indicated as black bars. Other regions of interest are the Tudor domain (red), poly-proline regions (green), the YG box (orange), and the cytoplasmic targeting motif (black). Point mutations identified in SMN1 genes of SMA patients are indicated below (Wirth 2000; Alias et al. 2008)

Fig. 2

Model of a putative function of SMN complexes in axonal RNA localization. Data from different labs suggest a model whereby SMN-associated RNP complexes contribute to the localization of β-actin mRNA and probably other transcripts. SMN may facilitate the assembly of RNA cargo molecules with different RNA-binding proteins, adaptor proteins, molecular motor proteins, translational components, and auxiliary factors required for efficient transport and/or local translation (Based on a model by Lei Xing.)

Fig. 3

SMN-containing granules are transported along motor axons. SMN is localized in granules that are actively transported into neuronal processes and growth cones (Zhang et al. 2006). Shown above are murine primary embryonic motor neurons expressing GFP from the motor neuron-specific HB9 promoter. SMN-containing granules stained with specific antibodies are present in the cell body, dendrites, and axon, including the growth cone (red). Size bar = 10 μm (photomicrograph provided by Lei Xing)