Uncovering the Links Between SMN Protein and Spinal Muscular Atrophy During COVID-19 Pandemic

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive weakness of the skeletal and respiratory muscles. The condition affects motor nerve cells in the spinal cord, slowly taking away the ability to walk, eat, and breathe. SMA is one of the most common inherited neuromuscular conditions, with an incidence of between 1/6,000 – 1/10,000 live births.

Spinal muscular atrophy is caused by deletion or mutation of the SMN1 gene, leading to a lack of functional SMN protein without which motor neurons cannot properly function and eventually die. It is a homozygous condition, so only manifests when there are two missing or mutated copies. The relatively high frequency of the condition is due to the fact that roughly 1/50 of the population carry a single mutated/deleted gene, and if both parents carry a mutated gene the chance of a child having the disease is 1 in 4.

Interestingly there is what might be described as a “back-up” gene called SMN2.  This can produce functional SMN protein, but only at a level of around 10% of that of the SMN1 gene, which is insufficient to fully replace the missing SMN protein. Varying levels of SMN protein production by the SMN2 gene are responsible for variations in the severity of clinical SMA.

What does the SMN protein do?

SMN is part of a protein complex that also includes a set of diverse proteins known as GEMINs (indeed SMN protein was previously known as GEMIN1). The SMN-GEMINs complex is vital for chaperoning the biogenesis of small nuclear ribonucleoproteins (snRNPs), which are crucial for pre-mRNA splicing (1). Alongside its key role in mRNA processing several other functions have more recently been ascribed to SMN, all indicating a key cellular function in regulating cellular protein homeostasis (reviewed in ref. 2).   The increasing recognition of the wider importance of SMN protein suggest that much further research is justified in this area. Whilst the majority of research to date has understandably been related to it’s link to SMA, more fundamental studies are clearly required.

Therapies for Spinal muscular atrophy

At present, there are several ways to manage SMA, such as nusinersen, an intrathecal injection of antisense oligonucleotide that target SMN2 pre-mRNA, onasemnogene abeparvovec-xioi, a single intravenous infusion of AAV9 containing the SMN1 transgene, and risdiplam (an orally-administered small molecular SMN2 splicing modifier). All of these treatments are very expensive (Nusinersin may cost up to £450,000 for a first year course) and their long-term effectiveness is unproven.

With this in mind there is much continuing research into new potential therapies. A recent study looking at the possibility of CRISPR mediated gene-editing has been published (3). There have also been discussions about the possibility of targeting other GEMIN protein family members (4).

Spinal muscular atrophy and GEMINs in autoimmunity

Another interesting aspect of the SMN protein complex is that it has been reported as a target for autoimmune responses, leading to cases of polymyositis including muscle weakness. The potential link to SMN function in motor neurones is intriguing.

In a key report autoantibodies were found against SMN protein itself, and also against GEMIN-1, GEMIN-2 and GEMIN-4 (7).

Antibodies to SMN and GEMIN proteins

Monoclonal antibodies specific for SMN protein and for the GEMIN proteins clearly have important roles in the study of these proteins, their function and their role in disease. The SMN specific antibody clone 2B1 has been used to purify SMN protein complexes for studies of autoimmunity, and importantly can be used to assess the levels of SMN protein in tissue samples, which can be directly correlated with disease severity.

At Immuquest we are pleased to be able to offer a number of highly specific antibodies to these proteins to help researchers with their ongoing studies