Abstract
Spinal muscular atrophy (SMA) is caused by homozygous mutation of the survival motor neuron 1 (SMN1) gene. Disease severity inversely correlates to the amount of SMN protein produced from the homologous SMN2 gene. We show that SMN protein is naturally released in exosomes from all cell types examined. Fibroblasts from patients or a mouse model of SMA released exosomes containing reduced levels of SMN protein relative to normal controls. Cells overexpressing SMN protein released exosomes with dramatically elevated levels of SMN protein. We observed enhanced quantities of exosomes in the medium from SMN-depleted cells, and in serum from a mouse model of SMA and a patient with Type 3 SMA, suggesting that SMN-depletion causes a deregulation of exosome release or uptake. The quantity of SMN protein contained in the serum-derived exosomes correlated with the genotype of the animal, with progressively less protein in carrier and affected animals compared to wildtype mice. SMN protein was easily detectable in exosomes isolated from human serum, with a reduction in the amount of SMN protein in exosomes from a patient with Type 3 SMA compared to a normal control. Our results suggest that exosome-derived SMN protein may serve as an effective biomarker for SMA.
Highlights
With an occurrence of 1 in 10,000 live births and a carrier frequency of 1 in 40, spinal muscular atrophy (SMA) is the most common cause of death by a genetic disease in newborns[1,2]
An antisense oligonucleotide (ASO) designed to promote retention of exon 7 in the mRNA transcript derived from the SMN2 gene, by the Food and Drug Administration in the USA has provided the first effective therapy to treat SMA32,33
We have shown that survival motor neuron (SMN) protein is released from cells in both microparticles and exosomes (Fig. 2)
Summary
With an occurrence of 1 in 10,000 live births and a carrier frequency of 1 in 40, spinal muscular atrophy (SMA) is the most common cause of death by a genetic disease in newborns[1,2]. One of the easiest and least-invasive methods to provide insight into disease severity and prognosis would be to identify a blood-based biomarker that accurately reflect the SMA disease state To this end, several researchers have analyzed peripheral blood mononuclear cells (PBMCs) from patients with SMA for a variety of disease markers, including total SMN transcript level, relative full-length versus SMNΔ7 mRNA transcript level, and protein level[41,42,43,44,45]. Several researchers have analyzed peripheral blood mononuclear cells (PBMCs) from patients with SMA for a variety of disease markers, including total SMN transcript level, relative full-length versus SMNΔ7 mRNA transcript level, and protein level[41,42,43,44,45] These studies demonstrated a trend between motor function and changes in several markers, no statistical correlation was observed. We evaluated the SMN protein content of exosomes isolated from tissue culture and animal models of SMA, and performed an analysis regarding whether exosome-derived SMN protein may be an effective biomarker for SMA
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