Abstract
Spinal muscular atrophy is a severe motor neuron disease caused by inactivating mutations in the SMN1 gene leading to reduced levels of full-length functional SMN protein. SMN is a critical mediator of spliceosomal protein assembly, and complete loss or drastic reduction in protein leads to loss of cell viability. However, the reason for selective motor neuron degeneration when SMN is reduced to levels which are tolerated by all other cell types is not currently understood. Widespread splicing abnormalities have recently been reported at end-stage in a mouse model of SMA, leading to the proposition that disruption of efficient splicing is the primary mechanism of motor neuron death. However, it remains unclear whether splicing abnormalities are present during early stages of the disease, which would be a requirement for a direct role in disease pathogenesis. We performed exon-array analysis of RNA from SMN deficient mouse spinal cord at 3 time points, pre-symptomatic (P1), early symptomatic (P7), and late-symptomatic (P13). Compared to littermate control mice, SMA mice showed a time-dependent increase in the number of exons showing differential expression, with minimal differences between genotypes at P1 and P7, but substantial variation in late-symptomatic (P13) mice. Gene ontology analysis revealed differences in pathways associated with neuronal development as well as cellular injury. Validation of selected targets by RT–PCR confirmed the array findings and was in keeping with a shift between physiologically occurring mRNA isoforms. We conclude that the majority of splicing changes occur late in SMA and may represent a secondary effect of cell injury, though we cannot rule out significant early changes in a small number of transcripts crucial to motor neuron survival.
Highlights
Autosomal recessive Spinal Muscular Atrophy (SMA) is a leading genetic cause of infant mortality, with a carrier frequency of 1:50 and an annual incidence of 1 in 10,000 live births [1]
An unresolved issue is whether loss of the general cellular function of Survival Motor Neuron (SMN) in spliceosomal assembly, which is predicted to result in widespread defects in mRNA splicing, is directly responsible for motor neuron death
Mouse models of SMA, which have reduced SMN levels, show a drop in small nuclear ribonuclear proteins (snRNPs) assembly activity as measured by in vitro assays, while steady state snRNP levels measured in tissues are only mildly reduced [14]
Summary
Autosomal recessive Spinal Muscular Atrophy (SMA) is a leading genetic cause of infant mortality, with a carrier frequency of 1:50 and an annual incidence of 1 in 10,000 live births [1]. The pathological correlate of these symptoms is selective loss of large alpha motor neurons in the ventral horn of the spinal cord. The vast majority of cases are caused by homozygous deletion of the survival motor neuron 1 (SMN1) gene [2] with subsequent reduction in levels of the SMN protein [3]. Complete loss of SMN, which is incompatible with life [4], is prevented by production of SMN from the SMN2 gene, a near identical paralogue of SMN1 which has arisen from an inverted duplication event in recent evolution. Disease severity is broadly proportional to residual SMN levels, which is a function of SMN2 copy number, other modifying factors are involved in some cases [8,9]
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