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Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick?

Key Points

  • Spinal muscular atrophy (SMA) is caused by reduced amounts of the ubiquitously expressed survival motor neuron protein (SMN). SMN functions in RNA metabolism, but the question of which aspect of its function is disrupted to give a motor neuron disease remains unanswered.

  • SMN functions in the assembly of Sm proteins onto small nuclear RNAs (snRNAs) during pre-mRNA splicing. It has been suggested that SMN might have a role in the assembly of other ribonucleoprotein (RNP) complexes.

  • SMA is caused by loss or mutation of SMN1 and retention of SMN2,leading to low SMN levels. Proteins that carry mild missense mutations complement SMN2 to restore assembly activity and give a mild phenotype.

  • Loss of SMN in all species results in lethality, indicating that SMN has an essential function. Animal models of SMA can be created by reducing the levels of SMN.

  • It has been proposed that reduction of SMN levels results in an alteration of the small nuclear ribonucleoprotein (snRNP) profile. This is supported by the correlation between snRNP assembly activity and SMA severity in mice; however, a clear indication of the downstream target genes that are affected is currently lacking.

  • SMN is found in axons of cultured cells, and a second hypothesis suggests that altered mRNA transport in axons may contribute to SMA. However, a clear indication of what SMN function is disrupted to alter mRNA transport is lacking.

  • SMN functions in the assembly of RNPs, but it remains unresolved whether it is an axonal or an snRNP component that is disrupted in SMA. Experiments showing a clear suppression of the phenotype by manipulating a particular pathway could be used to demonstrate the crucial pathway in SMA.

Abstract

Many neurogenetic disorders are caused by the mutation of ubiquitously expressed genes. One such disorder, spinal muscular atrophy, is caused by loss or mutation of the survival motor neuron1 gene (SMN1), leading to reduced SMN protein levels and a selective dysfunction of motor neurons. SMN, together with partner proteins, functions in the assembly of small nuclear ribonucleoproteins (snRNPs), which are important for pre-mRNA splicing. It has also been suggested that SMN might function in the assembly of other ribonucleoprotein complexes. Two hypotheses have been proposed to explain the molecular dysfunction that gives rise to spinal muscular atrophy (SMA) and its specificity to a particular group of neurons. The first hypothesis states that the loss of SMN's well-known function in snRNP assembly causes an alteration in the splicing of a specific gene (or genes). The second hypothesis proposes that SMN is crucial for the transport of mRNA in neurons and that disruption of this function results in SMA.

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Figure 1: Function of SMN in snRNP assembly.
Figure 2: SMN genes and protein structure.
Figure 3: Mechanisms proposed to explain how reduced SMN levels cause SMA.

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Acknowledgements

We would like to thank all members of the SMA community for many helpful discussions. Owing to limited space we have not quoted all literature in the field, and we apologize to those whose articles are not referenced. We would like to thank L. Pellizzoni for many helpful comments on the manuscript and M. Butchbach for figure 2. We would like to thank all members of our laboratories for many useful discussions, in particular V. McGovern, who has read and edited many portions of this article in various formats. The work in our laboratories has been supported by the US National Institute of Neurological Disorders and Stroke, Families of SMA, Fight SMA, the SMA Foundation, the Madison, Matthew, Preston and Cade & Katelyn funds and the SMA Angels.

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Correspondence to Arthur H. M. Burghes.

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Disruption of RNA metabolism in Neurological Disorders (PDF 264 kb)

Supplementary information S2 (box)

SMN and SnRNP assembly (PDF 198 kb)

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DATABASES

OMIM

amyotrophic lateral sclerosis

Huntington's disease

FURTHER INFORMATION

Arthur H. M. Burghes's homepage

Neuromuscular Disease Center web page on SMA

Glossary

Splicing

The removal of introns from pre-mRNA to obtain mRNA.

Missense mutation

A mutation that results in the substitution of an amino acid in a protein.

U small nuclear RNA

(U snRNA). A small nuclear RNA that is rich in uridine.

Sm proteins

Proteins that were first found as antigens in a patient with systemic lupus erythematosus, and were named after the patient. Sm and Sm-like (LSm) proteins constitute a group of RNA-binding proteins that have a common three-dimensional stucture and form a heptameric or hexameric ring.

Complementation

The ability of two mutant alleles to interact to produce a normal or milder phenotype. In general, this occurs when the mutations that give rise to the phenotype occur in two different genes. However, allelic complementation arises when different mutations in the same gene interact to produce a functional complex.

Tudor domain

A conserved stretch of 50 amino acids, originally found in the Tudor protein of Drosophila melanogaster, that is often found in proteins with known roles in RNA metabolism.

RNA granules

Cytoplasmic deposits that contain RNA. These can also be found in axons and dendrites. RNA in these granules may be transported to the distal axon for localized protein translation in the growth cone.

Autosomal recessive disorder

A disorder that requires both copies of a gene on an autosomal (non-sex) chromosome to be mutated.

Active zone

A portion of the presynaptic membrane that faces the postsynaptic density across the synaptic cleft. It constitutes the site of synaptic vesicle clustering, docking and neurotransmitter release.

Informational suppressor

A suppressor that will modify a phenotype in a non-gene-specific manner. For example, overexpression of plastin 3 may encourage axon growth, thereby rescuing the phenotypes caused by SMN deficiency and those caused by mutations in other genes.

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Burghes, A., Beattie, C. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick?. Nat Rev Neurosci 10, 597–609 (2009). https://doi.org/10.1038/nrn2670

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